Introduction: are current drug development programmes realising the full potential of new agents?

The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach.

The purpose of this review is to consider the issues for women related to participation in clinical trials that evaluate the management of breast cancer and provide some recommendations for future initiatives to address the identified areas of concern. The National Health and Medical Research Council (NHMRC) National Breast Cancer Centre hosted an international workshop to address the question "Clinical Trials in Breast Cancer: Should Women Take Part?" We also reviewed the literature on informed participation in clinical trials that was identified in a broadly based search that covered Medline, PsycLIT, and HealthPlan from 1986 to 1996. When women are asked to participate in a clinical trial, they are faced with a number of questions and dilemmas. These include issues related to the conduct and ethical considerations of the trial; the effect of participation or nonparticipation on treatment; the roles of the doctor as clinician and as researcher; the process of informed consent; the timing of the request for participation; and the benefits and costs of participation. A number of steps are identified that could help women decide whether to participate in clinical trials. These include provision of community information about clinical trials; establishment of independent brokers and registers for clinical trials; consumer review of information and protocols and involvement in trials; review of the role of ethics committees; collection of data about the proportion of women currently recruited to clinical trials, their reasons for participating or declining, and their views about the process of recruitment and participation; models for optimal practice in recruiting women to clinical trials and encouraging ongoing participation in trials; evidence-based communication skills training for clinicians to teach skills to inform women adequately of clinical trial participation; and auspicing and promotion of trials by an independent agency.

Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer

Breast cancer is not a single disease. Specific biological processes and distinct genetic pathways are associated with prognosis and sensitivity to chemotherapy and targeted agents in different subtypes of breast cancers. As a consequence, breast cancer can be classified by molecular events. A primary challenge for future drug development in breast cancer will be to distinguish genes and pathways that 'drive' cancer proliferation (drivers) from genes and pathways that have no role in the development of cancer (passengers). The identification of functional pathways that are enriched for mutated genes will select subpopulation of patients likely to be sensitive to biology-driven targeted agents. The selection of driver pathways in resistant tumors will permit to discover a biology-driven platform for new drug development to overcome resistance. We are moving in the era of stratified and personalized therapy. Personalized cancer therapy is based on the precept that detailed molecular characterization of the patient's tumor and its microenvironment will enable tailored therapies to improve outcomes and decrease toxicity. However, there are numerous challenges we need to overcome before delivering on the promise of personalized cancer therapy. These include tumor heterogeneity and molecular evolution, costs and potential morbidity of biopsies, lack of effective drugs against most genomic aberrations, technical limitations of molecular tests, and reimbursement and regulatory hurdles. Critically, successes and limitations surrounding personalized cancer therapy must be tempered with realistic expectations, which, today, encompass increased survival times for only a portion of patients.

Differential whole-genome doubling based signatures for improvement on clinical outcomes and drug response in patients with breast cancer

Does a young woman living with a smoker or taking a job working in a smoky bar have a greater chance of developing breast cancer? Some scientists believe that such situations can indeed raise a woman’s risk of developing breast cancer before the age of 50. Because epidemiological and toxicological studies show that women’s breast tissue may be especially sensitive to exposure to carcinogens prior to first pregnancy, these researchers contend that public education should be directed at alerting adolescents and young women to the potential risk. However, not everyone in the international public health community agrees that the evidence to date supports a link between passive smoking and breast cancer, and some say that women are being alarmed unnecessarily. This disagreement has sparked debate that is sometimes heated. The stakes are high because breast cancer is the most common cancer in women in industrialized countries, according to the WHO. It is the leading cancer killer of nonsmoking women, and second only to lung cancer deaths among women who smoke. Among the researchers interviewed for this article who disagree that there is enough evidence to link secondhand smoke (SHS) with breast cancer, the majority call the evidence to date “suggestive but not sufficient,” as the Surgeon General’s 2006 report, The Health Consequences of Involuntary Exposure to Tobacco Smoke, put it. That characterization is based largely on the fact that the research considered when the Surgeon General’s report was being amassed did not clearly link even active smoking to breast cancer. Researchers in this camp do, however, stress that ongoing campaigns to prohibit smoking in public will protect the whole of society against the wide variety of ills proven to be caused by SHS. These include lung cancer, cardiovascular disease, and sudden infant death syndrome, among others. A smaller group contends that the question of whether or not SHS causes breast cancer is a political issue with the potential to compromise the scientific process. “A premature decision about causality could jeopardize the credibility of the entire review process and all of the other, established effects of secondhand smoke,” says Michael Thun, national vice president of epidemiology and surveillance research for the American Cancer Society. Adds Valerie Beral, director of the University of Oxford Cancer Research UK Epidemiology Unit, “To prematurely come to conclusions about the causation when there is a big division in the scientific community . . . is bad science.” Thun debated the subject in a series of public forums held in conjunction with scientific meetings. Taking the opposing view was Kenneth C. Johnson, a research scientist with the Public Health Agency of Canada, who was one of the first scientists to discern a potential link. During the debates, Johnson pointed out there are about the same number of studies linking breast cancer to passive smoking as there were linking lung cancer to SHS in 1986, when the Surgeon General concluded that passive smoking caused lung cancer. Johnson also says that more of the breast cancer studies are statistically significant, and that the estimated risk for breast cancer is higher.

Standardized definitions of breast cancer clinical trial end points must be adopted to permit the consistent interpretation and analysis of breast cancer clinical trials and to facilitate cross-trial comparisons and meta-analyses. Standardizing terms will allow for uniformity in data collection across studies, which will optimize clinical trial utility and efficiency. A given end point term (eg, overall survival) used in a breast cancer trial should always encompass the same set of events (eg, death attributable to breast cancer, death attributable to cause other than breast cancer, death from unknown cause), and, in turn, each event within that end point should be commonly defined across end points and studies. A panel of experts in breast cancer clinical trials representing medical oncology, biostatistics, and correlative science convened to formulate standard definitions and address the confusion that nonstandard definitions of widely used end point terms for a breast cancer clinical trial can generate. We propose standard definitions for efficacy end points and events in early-stage adjuvant breast cancer clinical trials. In some cases, it is expected that the standard end points may not address a specific trial question, so that modified or customized end points would need to be prospectively defined and consistently used. The use of the proposed common end point definitions will facilitate interpretation of trial outcomes. This approach may be adopted to develop standard outcome definitions for use in trials involving other cancer sites.

Background:Neo-tAnGo, a National Cancer Research Network (NCRN) multicentre randomised neoadjuvant chemotherapy trial in early breast cancer, enroled 831 patients in the United Kingdom. We report a central review of post-chemotherapy histopathology reports on the surgical specimens, to assess the presence and degree of response.Methods:A central independent two-reader review (EP and HME) of histopathology reports from post-treatment surgical specimens was performed. The quality and completeness of pathology reporting across all centres was assessed. The reviews included pathological response to chemotherapy (pathological complete response (pCR); minimal residual disease (MRD); and lesser degrees of response), laterality, the number of axillary metastases and axillary nodes, and the type of surgery. A consensus was reached after discussion.Results:In all, 825 surgical reports from 816 patients were available for review. Out of 4125 data items there were 347 discrepant results (8.4% of classifications), which involved 281 patients. These involved grading of breast response (169 but only 9 involving pCR vs MRD); laterality (6); presence of axillary metastasis (35); lymph node counts (108); and type of axillary surgery (29). Excluding cases with pCR, only 45% of reports included any comment regarding response in the breast and 30% in the axillary lymph nodes.Conclusion:We found considerable variability in the completeness of reporting of surgical specimens within this national neoadjuvant breast cancer trial. This highlights the need for consensus guidelines among trial groups on histopathology reporting, and the participation of histopathologists throughout the development and analysis of neoadjuvant trials.

Purpose Observational study evidence has associated overweight/obesity with decreased survival in women with breast cancer and with several other cancers. Although full-scale, definitive weight loss adjuvant intervention trials with cancer end points remain to be conducted, a number of randomized controlled trials have evaluated weight loss interventions in survivors of cancer in women. Findings from these trials in breast, endometrial, and ovarian cancer are reviewed. Methods A systematic review of randomized controlled clinical trials evaluating weight loss interventions was updated (for studies published 2013 to 2016), and clinical trials registers were searched for ongoing trials. Results Six new randomized trials in breast cancer survivors and two randomized trials in endometrial cancer survivors were identified. Evidence from these trials and the 10 earlier randomized trials in female cancer survivors provide support for the feasibility of recruiting women closer to the cancer diagnosis and efficacy for achieving weight loss, in particular with telephone-based interventions, and have identified the challenge of achieving significant weight loss in African American cancer survivors and of maintaining weight loss in any cancer survivor group. Seven ongoing randomized trials are evaluating the influence of weight loss interventions on cancer end points (five in breast cancer, one in ovarian cancer, and one in endometrial cancer). Conclusion After a decade of preliminary studies, ongoing randomized, controlled clinical trials will potentially provide definitive assessment of whether weight loss can improve breast cancer clinical outcome. Longer-term interventions (> 2 years' duration) may be needed to optimize weight loss maintenance and any potential benefits on cancer end points.

PARP is an enzyme involved in sensing single-stranded DNA breaks and plays a critical role in the organization of DNA damage repair. Several PARP inhibitors have been developed for clinical use, particularly in breast and ovarian cancers with BRCA mutations. Despite the scientific rationale and promising early clinical results with PARP inhibitors, more advanced clinical trials in breast cancer have been disappointing. One of the questions arising from these trials is to better understand why the PARP inhibitors failed. We used a window-chamber system in mice to image the distribution and function of model PARP inhibitors such as AZD2281-Bodipy. Specifically, we measured the kinetics of vascular, cellular, and subcellular uptake and distribution of AZD2281-Bodipy in breast (MDA-MB-231, MDA-MB-436) and ovarian (OVCAR429, A2780) tumors over time. Additionally, using the fluorescently-labeled inhibitor, we were able to examine the heterogeneity of AZD2281 localization in single cancer cells in vivo. Our data provide the first example of single-cell distribution of fluorescent small molecule inhibitors. When coupled with reporter cell lines (e.g. for apoptosis, DNA damage, autophagy, and senescence), this approach will be a powerful tool to understand drug action in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4293. doi:1538-7445.AM2012-4293

Commentary on ‘Problems associated with randomized controlled clinical trials in breast cancer’ (A.E. Johnson, Journal of Evaluation in Clinical Practice 4, 119–126, this issue)

Introduction: The aim of this prospective study was to evaluate the correlation of primary (1ry)tumor metabolic activity parameters maximum standardized uptake value (SUVmax) and tumor SUVmax/liver average SUV ratio (TLR) in initial staging 18F-fluorodeoxyglucose (FDG) positron emission tomography / computerized tomography (PET/CT) scan with clinical, histopathological and molecular characteristics of breast cancer (BC) patients. Material and Methods: Initial staging PET/CT was performed in 40 cases with different stages of BC in the supine position. Tumor FDG uptake was qualitatively evaluated and quantitatively assessed using SUVmax and TLR. Results: Forty female patients with newly diagnosed BC were enrolled in our study, age range from 31-78 (mean 50.5 +/- SD11.7). All the 1ry tumors were detected with mean SUVmax 10.8(+/-SD 7.9). The mean /median SUVmax values of 1ry tumor was higher in premenopausal, stage III& IV, Estrogen Receptors negative(ER-), Progesteron Receptors negative(PR-), Her2neu positive patients, high nuclear grade (GIII), in triple negative molecular subgroup (TN), positive axillary nodal (ALNs)metastases, and (P value = 0.003, 0.017, 0.113, 0.089 0.01,0.002, 0.007 & 0.016 respectively). The mean/median TLR values was higher in premenopausal and Her2neu positive, GIII, TN molecular subtype patients, stage III& IV and in patients with positive ALNs, ER- &PR - patients (P value = 0.002, 0.0476, 0.005, 0.018, 0.039 and 0.022, 0.095 & 0.129 respectively). SUVmax of the 1ry lesion and TLR were moderately negatively correlated with the age of the patients (P value = 0.005 and 0.008 respectively), also they were moderately positively correlated with the size of the1ry tumor (P value = 0.019 and 0.036 respectively). Conclusion: The SUVmax of the 1ry tumor and TLR values had similar significant associations with different prognostic factors in BC

Studies of the etiology, early detection, and prevention of breast cancer reported in the past year are reviewed in this paper. Studies of the etiology of breast cancer include reports on genetic and environmental factors. A major advance in the study of inherited forms of breast and ovarian cancer occurred with the identification of the BRCA1 gene. A second breast cancer susceptibility gene, the BRCA2 gene, was localized to chromosome 13q12-13. Multiple mutations in the BRCA1 gene have been identified, presenting a challenge for the development of predictive testing. Controversy continues over the association between hormone replacement therapy and the development of breast cancer. A study of exercise suggests a strong protective effect against the development of early onset breast cancer. Recent studies have failed to find a strong link between dietary fat intake and the development of breast cancer. A meta-analysis of studies of the efficacy of screening for the prevention of breast cancer mortality demonstrates a significant reduction in mortality among women 50 years of age and older. A lowering of breast cancer mortality for women aged 40 to 49 was only demonstrated after 10 to 12 years of follow-up. The risks and benefits of tamoxifen therapy, a potential breast cancer chemoprevention agent, continue to be clarified. Adverse effects on the endometrium, including an increased risk of endometrial cancer, have been reported. Beneficial effects include an improved cardiovascular risk profile and preservation of bone mineral density among postmenopausal women.

Peripheral neuropathy is considered a common complication of taxanes, which in severe cases can limit the optimal treatment. Our study aimed to evaluate the efficacy of memantine in the prevention of docetaxel-induced neuropathy in patients with breast cancer. In this randomised clinical trial, 40 women between the ages of 18 and 64 years with non-metastatic breast cancer were included. All patients were treated with the AC-T regimen (with docetaxel). Patients in the intervention group received memantine 20 mg for 8 weeks from the beginning of the first cycle of docetaxel. Patients in the control group did not receive any medication for the prevention of neuropathy. To assess the neuropathy, Douleur Neuropathies 4 (DN4) and Common Terminology Criteria for Adverse Events (CTCAE) questionnaires were used at baseline, 1 month (follow-up 1), 3 months (follow-up 3) and 6 months (follow-up 6) after the study initiation. The DN4 score was remarkably less in the memantine group in follow-up one (p=0.033) and three (p<00.1). The CTCAE follow-up score did not change during the study. Neuropathy duration and onset were significantly different between the intervention and control groups (p=0.050 and p=0.001, respectively). Out of 40 patients, 8 (40%) in the memantine group and 2 (10%) in the control group did not experience neuropathy. Based on the results, memantine 20 mg/day may be effective in reducing the risk of docetaxel-induced neuropathy in patients with breast cancer, but further studies are needed to confirm these findings.Based on the findings, memantine at a dosage of 20 mg/day may exhibit a potential preventive effect in patients with breast cancer undergoing treatment with docetaxel as part of their chemotherapy regimen. IRCT20160310026998N9.

Introduction: Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and results in disproportionally higher mortality compared to other breast cancers. Moreover, there is a paucity of therapies for this subtype of breast cancer resulting primarily from an inadequate understanding of the transcriptional differences that differentiate TNBC from normal breast. Using next-generation RNA-seq, we embarked on a study to compare the transcriptomes of TNBC and normal breast to comprehensively identify dysregulated networks, pathways, transcription factors, and high connectivity drug targets that can be exploited for therapeutic discovery. Methods: cDNA libraries from 10 normal breast tissues from the Susan G. Komen Tissue Bank at the IU Simon Cancer Center and 10 TNBC tumors were sequenced on an Applied Biosystems (ABI) SOLiD3 sequencer. Mapping of reads to the human genome (hg18) was performed using ABI BioScope 1.2; differential gene expression was analyzed using Partek Genomics Suite; and network, pathway, and transcription factor analysis was performed using Ingenuity Systems iReport and IPA 9.0. Results: Canonical pathway analysis revealed highly elevated and enriched expression in BRCA/DNA repair pathways, PI3K/AKT, and integrin signaling. Particularly, targeting BRCA/DNA repair pathways with PARP inhibitors has demonstrated some clinical success. Our pathway analysis reveals additional targets: ATM, CHK1/2, &amp; PLK1 that are highly overexpressed and are integral to the BRCA pathway. To determine key regulators of our dataset, we employed IPA's transcription factor (TF) analysis that utilizes a literature knowledge base to identify TFs that explain a set of differential expression data, and classifies them as either activated or inhibited. We observed that TP53, RB1, &amp; CDKN2A were significantly inhibited. This is congruent with current literature showing that TP53 &amp; RB1 as the most predominantly mutated genes in TNBC. In terms of activation, TBX2 and c-MYC were significantly activated in our dataset, suggesting a highly pro-tumorigenic transcriptional programme. In addition, RNA-seq detects pre-miRNAs. When integrated into the analysis, the top ranked network reveals a large set of dysregulated miRNAs secondary to inhibited TP53. When looking at druggable kinases, we performed a connectivity analysis to determine major hub proteins. Our top three kinases were SRC, IKBKE, and AKT1. Of note AKT inhibitors have recently entered early phase clinical trials in breast cancer. Conclusions: Network analysis reveals a concerted programme of proteins and transcription factors that drive a highly pro-tumorigenic phenotype revolving around nonfunctional TP53, and upregulated PI3K/AKT &amp; DNA damage repair pathways. The analysis reveals additional DNA damage repair proteins in addition to PARP and highly connected kinases as potential drug targets for TNBC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-409. doi:1538-7445.AM2012-LB-409