Photon Absorption Remote Sensing Imaging of Breast Needle Core Biopsies Is Diagnostically Equivalent to Gold Standard H&E Histologic Assessment.

Photon absorption remote sensing (PARS) is a new laser-based microscope technique that permits cellular-level resolution of unstained fresh, frozen, and fixed tissues. Our objective was to determine whether PARS could provide an image quality sufficient for the diagnostic assessment of breast cancer needle core biopsies (NCB). We PARS imaged and virtually H&E stained seven independent unstained formalin-fixed paraffin-embedded breast NCB sections. These identical tissue sections were subsequently stained with standard H&E and digitally scanned. Both the 40× PARS and H&E whole-slide images were assessed by seven breast cancer pathologists, masked to the origin of the images. A concordance analysis was performed to quantify the diagnostic performances of standard H&E and PARS virtual H&E. The PARS images were deemed to be of diagnostic quality, and pathologists were unable to distinguish the image origin, above that expected by chance. The diagnostic concordance on cancer vs. benign was high between PARS and conventional H&E (98% agreement) and there was complete agreement for within-PARS images. Similarly, agreement was substantial (kappa > 0.6) for specific cancer subtypes. PARS virtual H&E inter-rater reliability was broadly consistent with the published literature on diagnostic performance of conventional histology NCBs across all tested histologic features. PARS was able to image unstained tissues slides that were diagnostically equivalent to conventional H&E. Due to its ability to non-destructively image fixed and fresh tissues, and the suitability of the PARS output for artificial intelligence assistance in diagnosis, this technology has the potential to improve the speed and accuracy of breast cancer diagnosis.

Assessment of ERBB2/HER2 Status in HER2-Equivocal Breast Cancers by FISH and 2013/2014 ASCO-CAP Guidelines.

Importance: The 2013/2014 American Society of Clinical Oncology and College of American Pathologists (ASCO-CAP) guidelines for HER2 testing by fluorescence in situ hybridization (FISH) designated an "equivocal" category (average HER2 copies per tumor cell ≥4-6 with HER2/CEP17 ratio <2.0) to be resolved as negative or positive by assessments with alternative control probes. Approximately 4% to 12% of all invasive breast cancers are characterized as HER2-equivocal based on FISH. Objective: To evaluate the following hypotheses: (1) genetic loci used as alternative controls are heterozygously deleted in a substantial proportion of breast cancers; (2) use of these loci for assessment of HER2 by FISH leads to false-positive assessments; and (3) these HER2 false-positive breast cancer patients have outcomes that do not differ from clinical outcomes for patients with HER2-negative breast cancer. Design, Setting, and Participants: We retrospectively assessed the use of chromosome 17 p-arm and q-arm alternative control genomic sites (TP53, D17S122, SMS, RARA, TOP2A), as recommended by the 2013/2014 ASCO-CAP guidelines for HER2 testing, in patients whose data were available through Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and whose tissues were available through the Breast Cancer International Research Group clinical trials. We used data from an international cohort database of invasive breast cancers (1980 participants) and international clinical trial of adjuvant chemotherapy in invasive, node-positive breast cancer patients. Main Outcomes and Measures: The primary objectives were to (1) assess frequency of heterozygous deletions in chromosome 17 genomic sites used as FISH internal controls for evaluation of HER2 status among HER2-equivocal cancers; (2) characterize impact of using deleted sites for determination of HER2-to-internal-control-gene ratios; (3) assess HER2 protein expression in each subgroup; and (4) compare clinical outcomes for each subgroup. Results: Of the 1980 patients in METABRIC,1915 patients were fully evaluated. In addition, 100 HER2-equivocal breast cancers by FISH and 100 comparator FISH-negative breast cancers from the BCIRG-005 trial were analyzed. Heterozygous deletions, particularly in specific p-arm sites, were common in both HER2-amplified and HER2-not-amplified breast cancers. Use of alternative control probes from these regions to assess HER2 by FISH in HER2-equivocal as well as HER2-not-amplified breast cancers resulted in high rates of false-positive ratios (HER2-to-alternative control ratio ≥2.0) owing to heterozygous deletions of control p-arm genomic sites used in ratio denominators. Misclassification of HER2 status was observed not only in breast cancers with ASCO-CAP equivocal status but also in breast cancers with an average of fewer than 4.0 HER2 copies per tumor cell when using alternative control probes. Conclusions and Relevance: The indiscriminate use of alternative control probes to calculate HER2 FISH ratios in HER2-equivocal breast cancers may lead to false-positive interpretations of HER2 status resulting from unrecognized heterozygous deletions in 1 or more of these alternative control genomic sites and incorrect HER2 ratio determinations.

The Economic Contribution of Industry-Sponsored Pharmaceutical Clinical Trials.

PURPOSE: In pharmaceutical clinical trials, industrial sponsors pay for study drugs and related healthcare services. We conducted a study to determine industry's economic contribution of these trials to the Alberta healthcare system.  Methods: We used data from two trial centers for cancer and non-cancer trials at the University of Alberta. For each trial (cancer, non-cancer), we calculated the cost of drugs provided by the sponsors using the market price, the cost of clinical services, and the cost of administrative services that they paid. We extrapolated these results to all trials in Alberta based on information obtained from the registration website ClinicalTrials.gov.  Results: Our sample consisted of 40 non-cancer and 39 cancer drug trials which were initiated in 2012. The monetary value of the industry sponsors' contribution was $799,055 per non-cancer and $630,243 per cancer drug trial. Drugs (in-trial and post-trial) accounted for 84% of the total contribution of the non-cancer drug trials whereas it represented 93% of all trial-related contributions in the cancer category. The total province-wide contribution of industry-sponsored drug trials which were initiated in 2012 was estimated to be $101 million, including open-label drugs in the non-cancer category.  Conclusions: Industry-sponsored pharmaceutical trials represent a major economic contributor to clinical research within the province.

The Alberta Moving Beyond Breast Cancer (AMBER) Cohort Study: Recruitment, Baseline Assessment, and Description of the First 500 Participants.

BACKGROUND: To our knowledge, the Alberta Moving Beyond Breast Cancer (AMBER) Study is the first and only prospective cohort study of breast cancer survivors that includes objectively-measured physical activity (PA), sedentary behavior, health-related fitness (HRF), and biologic mechanisms focused on understanding breast cancer outcomes. The purpose of the present study was to report on the feasibility of recruitment, baseline measurement completion, and the representativeness of the first 500 participants. METHODS: AMBER is enrolling newly diagnosed stage I (≥T1c) to IIIc breast cancer survivors in Alberta, Canada. Baseline assessments are completed soon after diagnosis and include cardiorespiratory fitness, musculoskeletal fitness, body composition, objective and self-reported PA and sedentary behavior, lymphedema, and blood collection. RESULTS: Between July 2012 and November 2014, AMBER recruited its first 500 participants from a pool of 1,447 (35 %) eligible breast cancer survivors. Baseline HRF assessments were completed on ≥85 % of participants with the exception of upper body strength. Collection of ≥4 days/week of monitoring for the Actigraph GT3X® and ActivPAL® were obtained from 90 % of participants. Completion rates were also high for blood (99 %), lymphedema (98 %), and questionnaires (95 %) including patient-reported outcomes and correlates of exercise. The first 500 participants in AMBER are an average age of 56 years, 60 % are overweight or obese, and 58 % have disease stage II or III. CONCLUSION: Despite the modest recruitment rate and younger age, AMBER has demonstrated that many newly diagnosed breast cancer survivors are willing and able to complete a wide array of sophisticated and physically demanding HRF and PA assessments soon after diagnosis. AMBER is a unique breast cancer survivor cohort that may inform future randomized controlled trials on lifestyle and breast cancer outcomes as well as PA behavior change in breast cancer survivors. Moreover, AMBER may also inform guidelines on PA, sedentary behavior, and HRF for improving breast cancer outcomes and survivorship.

Evaluating the role of point source discharges informs statewide nutrient control policy in Utah.

An evaluation of costs, rate, and environmental impacts of upgrading publically owned treatment works (POTWs) in the State of Utah to four levels of nutrient control allowed a variety of nutrient control policies to be assessed. Upgrade costs and rate impacts indicated that costs would be within a defined range for many POTWs, especially with design capacities greater than 40,000 m3/day (-10 mgd). However, costs were significantly higher for some POTWs with lower design capacities, and nutrient upgrades to the most stringent levels would not be affordable for these communities, representing about 15 percent of the service population. The resulting equity issues can be addressed through hardship grants program and/or regulations based on a trading scheme. Analysis demonstrated that trading offers advantages, including cost efficiency and flexibility to accommodate further nutrient reductions and population growth, and greater ability to interface with urban and rural nonpoint nutrient control. Currently, the State of Utah is establishing technology-based nutrient limits that can be affordably implemented at all POTWs in phases. Additionally, a multi-faceted approach is being evaluated that will consider prioritized watershed-scale strategies, point and nonpoint sources of pollution, ecological and socioeconomic implications, and stakeholder participation in nutrient reduction programs.

Adjuvant targeted therapy in early breast cancer.

For this review, the authors appraised the evidence for adjuvant trastuzumab therapy in early breast cancer. There was level 1 evidence to support the routine use of 1 year of adjuvant trastuzumab in conjunction with chemotherapy for women with human epidermal growth factor receptor 2 (HER-2)-positive early breast cancer. The relative benefits of concurrent versus sequential administration remained unclear; however concurrent administration permitted the earliest possible intervention with trastuzumab with possible superiority. There was evidence to support the use of trastuzumab in both lymph node-positive and high-risk lymph node-negative patients, and preliminary data suggested that all patient subgroups that were eligible for the trials benefit equally from trastuzumab. Adjuvant trastuzumab was associated with a risk of cardiotoxicity, the long-term impact of which remains largely unknown. Routine cardiac risk assessment considering left ventricular ejection fraction, age, and prior history of cardiac events is recommended along with the selection of trastuzumab-based regimens that minimize cardiotoxicity. Trastuzumab acquisition costs for 1 year of therapy were the largest component of treatment costs.

Analyzing theoretical mechanisms of physical activity behavior change in breast cancer survivors: results from the activity promotion (ACTION) trial.

BACKGROUND: We previously reported that a physical activity (PA) behavior change intervention based on the theory of planned behavior (TPB) increased PA and quality of life in breast cancer survivors. PURPOSE: To examine the effects of our interventions on TPB variables and to determine if PA at 12 weeks follow-up was mediated by TPB variables at 4 weeks. METHODS: Breast cancer survivors (N = 377) were randomly assigned to receive either a standard public health recommendation for PA (SR group), a step pedometer alone, or one of two TPB-based behavior change interventions consisting of print materials (alone or combined with a step pedometer). For the purpose of this study, we compared the two TPB-based intervention groups (INT group) to the SR group. RESULTS: Compared to the SR group, the INT group reported more favorable changes in instrumental attitude (mean difference = 0.13; 95% CI = -0.01 to 0.23; d = 0.19; p = 0.077), intention (mean difference = 0.33; 95% CI = 0.10 to 0.56; d = 0.33; p = 0.006), and planning (mean difference = 0.39; 95% CI = 0.04 to 0.73; d = 0.26; p = 0.027). Mediation analyses indicated that both planning and intention partially mediated the effects of the intervention on PA at 12 weeks. CONCLUSIONS: Our TPB-based behavior change intervention resulted in small improvements in the TPB constructs that partially mediated the effects of our intervention on PA behavior. Additional research with the TPB is warranted.

Barriers to supervised exercise training in a randomized controlled trial of breast cancer patients receiving chemotherapy.

BACKGROUND: Exercise adherence is a challenge for breast cancer patients receiving chemotherapy but few studies have identified the key barriers. PURPOSE: In this paper, we report the barriers to supervised exercise in breast cancer patients participating in a randomized controlled trial. METHODS: Breast cancer patients initiating adjuvant chemotherapy (N = 242) were randomly assigned to usual care (n = 82) or supervised resistance (n = 82) or aerobic (n = 78) exercise. Participants randomized to the two exercise groups (n = 160) were asked to provide a reason for each missed exercise session. RESULTS: The two exercise groups attended 70.2% (5,495/7,829) of their supervised exercise sessions and provided a reason for missing 89.5% (2,090/2,334) of their unattended sessions. The 2,090 reasons represented 36 different barriers. Feeling sick (12%), fatigue (11%), loss of interest (9%), vacation (7%), and nausea/vomiting (5%) accounted for the most missed exercise sessions. Disease/treatment-related barriers (19 of the 36 barriers) accounted for 53% (1,102/2,090) of all missed exercise sessions. Demographic and medical variables did not predict the types of exercise barriers reported. CONCLUSIONS: Barriers to supervised exercise in breast cancer patients receiving chemotherapy are varied but over half can be directly attributed to the disease and its treatments. Behavioral support programs need to focus on strategies to maintain exercise in the face of difficult treatment side effects.