Phase Ib trial of inhaled iloprost for the prevention of lung cancer with predictive and response biomarker assessment.

Introduction: Iloprost, a prostacyclin analog, has lung cancerpreventive activity in preclinical models and improved dysplasia in former smokers in a phase IIb trial. Oral iloprost is currently unavailable. We performed a phase Ib trial of inhaled iloprost in former smokers to assess tolerance and compliance. Methods: Participants self-administered nebulized iloprost (5ug) or placebo four (QID) or two (BID) times daily. As QID dose was well tolerated and due to expiration of the placebo, the BID dosing and placebo were eliminated early on in the trial. Bronchoscopy with biopsyat six standard sites was performed at treatment initiation and two months post-iloprost, with exploratory histological analysis. Bulk RNA sequencing, single cell RNA sequencing and an in vitro assay of epithelial progenitor cell iloprost response were performed on a subset of biopsies in an exploratory investigation of response mechanisms and predictive biomarkers. Results and discussion: Thirty-four of a planned 48 participants were recruited to the trial.Inhaled iloprost was well tolerated with no adverse events > grade 2. Compliance was 67% in the QID group. The trial was not powered to detect histologic response and none was found. Bulk RNA sequencing of biopsies pre/post iloprost suggest that iloprost is immunomodulatory and downregulates cell proliferation pathways. Single cell RNA sequencing showed an increase in CD8-positive T cells with upregulation of genes in interferon γ signaling. In vitro iloprost response by epithelial progenitor cells correlated with histologic response with kappa coefficient of 0.81 (95% CI 0.47, 1.0). Inhaled iloprost was well tolerated with suboptimal compliance. Molecular analysis suggested that iloprosthas immunomodulatory and antiproliferative effects.The progenitor cell iloprost response assay may be a promising avenue to develop predictive biomarkers. Clinical trial registration: https://clinicaltrials.gov/study/NCT02237183, identifier NCT02237183.

Using ecological momentary assessment to understand associations between daily physical activity and symptoms in breast cancer patients undergoing chemotherapy.

PURPOSE: Understanding real-time relationships between physical activity (PA) and symptoms during chemotherapy (CT) could have important implications for intervention. This study used ecological momentary assessment to examine the relationship between objective PA and symptoms during CT. METHODS: Breast cancers patients (n = 67; Mage = 48.6 (SD = 10.3)) participated in data collection at three time points during CT: beginning, middle, and end. At each time point, participants answered four prompts assessing symptoms and wore an accelerometer for 10 days (3 days pre-CT, day of CT, and 6 days post-CT). Multilevel linear regression models examined the between- and within-person associations between moderate to vigorous (MVPA) and light-intensity physical activity (LPA) and same and next-day symptom ratings controlling for covariates. RESULTS: On days when individuals engaged in more LPA or MVPA, separately, they reported improved affect, anxiety, fatigue, physical functioning (walking and activities of daily living), pain, and cognition that day (p < 0.001 for all). Findings were consistent for next-day symptom ratings with the exception that only previous day LPA was related to next-day fatigue and neither LPA nor MVPA were related to next-day cognition (p < 0.001 for all). No between-person effects were found. CONCLUSIONS: Within person higher than usual PA on a given day, regardless of intensity, is associated with improved symptoms ratings on the current and next day. IMPLICATIONS FOR CANCER SURVIVORS: Encouraging breast cancer patients undergoing CT to engage in daily PA could help manage CT-associated symptoms.

High-Resolution Full-3D Specimen Imaging for Lumpectomy Margin Assessment in Breast Cancer.

BACKGROUND: Two-dimensional (2D) specimen radiography (SR) and tomosynthesis (DBT) for breast cancer yield data that lack high-depth resolution. A volumetric specimen imager (VSI) was developed to provide full-3D and thin-slice cross-sectional visualization at a 360° view angle. The purpose of this prospective trial was to compare VSI, 2D SR, and DBT interpretation of lumpectomy margin status with the final pathologic margin status of breast lumpectomy specimens. METHODS: The study enrolled 200 cases from two institutions. After standard imaging and interpretation was performed, the main lumpectomy specimen was imaged with the VSI device. Image interpretation was performed by three radiologists after surgery based on VSI, 2D SR, and DBT. A receiver operating characteristic (ROC) curve was created for each method. The area under the curve (AUC) was computed to characterize the performance of the imaging method interpreted by each user. RESULTS: From 200 lesions, 1200 margins were interpreted. The AUC values of VSI for the three radiologists were respectively 0.91, 0.90, and 0.94, showing relative improvement over the AUCs of 2D SR by 54%, 13%, and 40% and DBT by 32% and 11%, respectively. The VSI has sensitivity ranging from 91 to 94%, specificity ranging from 81 to 85%, a positive predictive value ranging from 25 to 30%, and a negative predicative value of 99%. CONCLUSIONS: The ROC curves of the VSI were higher than those of the other specimen imaging methods. Full-3D specimen imaging can improve the correlation between the main lumpectomy specimen margin status and surgical pathology. The findings from this study suggest that using the VSI device for intraoperative margin assessment could further reduce the re-excision rates for women with malignant disease.

Breast cancer risk assessment and management programs: A practical guide.

Breast cancer risk assessment continues to evolve as emerging knowledge of breast cancer risk drivers and modifiers enables better identification of high-risk women who may benefit from increased screening or targeted risk-reduction protocols. The ongoing development of breast cancer Risk Assessment and Management Programs (RAMPs) presents an opportunity to decrease breast cancer disease incidence with evidence-based interventions. The goal of this review was to provide a practical guide for providers seeking to establish or update a breast cancer risk assessment and management program. We outline genetic/familial, personal, reproductive, and lifestyle-related factors while discussing the incorporation of risk modeling for precise risk estimate personalization. We further describe the process for determining a risk management plan: information gathering, generation of a risk profile, and articulation and implementation of risk reduction. We also include an overview of clinical workflows in breast cancer management programs and underlines the logistics of establishing a program as well as general principles for guiding the formulation of an individualized risk management plan. We discuss practical considerations, such as clinic structure and operation, allocation of resources, and patient education. Other critical aspects of program design, including identification of the target population, delineation of the core components of the clinical experience, definition of provider roles, description of referral mechanisms, and the launching of a marketing plan are also addressed. The process of risk assessment is both anxiety-provoking and empowering for women at increased risk. New knowledge has enabled strategies to both understand the risk and control it through evidence-based risk management. These benefits can now be realized by an increasing number of unaffected, high-risk patients collaborating with risk management practitioners. Continuation of these efforts will lead to further progress in both risk stratification and risk management of women at elevated breast cancer risk in the near future.

A novel and cost-effective ex vivo orthotopic model for the study of human breast cancer in mouse mammary gland organ culture.

Mouse mammary organ culture (MMOC) is used to evaluate the efficacy of chemopreventive agents against the development of carcinogen-induced preneoplastic lesions and is highly correlative to in vivo carcinogenesis models. Here, we developed a new ex vivo MMOC model, by introducing human breast cancer cells into the mouse mammary gland. This novel model, termed human breast cancer in MMOC (BCa-MMOC), mimics in vivo orthotopic breast cancer mouse models. To develop this model, estradiol- and progesterone-sensitized female mice were injected with letrozole-sensitive and -resistant T47D breast cancer cells in the mammary glands and then euthanized. The glands were cultured in vitro with hormone-supplemented media. On day 25, the glands were fixed and processed by histopathology and immunohistochemistry to evaluate for the presence of T47D cells, growth pattern, cancer markers and estradiol responsiveness. Histopathological analyses demonstrated an identical pattern of growth between the breast cancer cells injected ex vivo and in vivo Interestingly, clusters of cancer cells in the mammary gland stroma appeared similar to those observed in human breast tumors. The injected T47D cells survived and proliferated for 15 days maintaining expression of estrogen receptor alpha (ER), progesterone receptor (PR), epidermal growth factor receptor (EGFR), and aromatase. The aromatase-overexpressing T47D grown in the BCa-MMOC sufficiently metabolized estrogen, resulting in enhanced cell proliferation, induction of estrogen target genes (i.e. ER and PR-B), and showed typical changes to estrogenic milieu. In summary, here we show a novel, inexpensive ex vivo model, to potentially study the effects of therapeutic agents on cancer cells grown in an orthotopic micromilieu.This article has an associated First Person interview with the first author of the paper.

Trends in adherence to NCCN guidelines for breast conserving therapy in women with Stage I and II breast cancer: Analysis of the 1998-2008 National Cancer Data Base.

OBJECTIVE: To examine temporal trends in guideline adherence for breast cancer local therapy, by race/ethnicity, socioeconomic and insurance status. BACKGROUND: Treatment guidelines recommend breast conserving therapy (BCT) for women with small cancers, but have been unevenly applied. A better understanding of time-trends in guideline adherence may point to interventions for correction. METHODS: Patients with tumors ≤2 cm (n = 1,081,075) were identified from 1123 NCDB hospitals, dividing the interval 1998-2011 into 5 segments. Significant differences in rates of guideline adherence over time for race/ethnicity, quartiles of income, education, and insurance status were identified using Chi-square tests. Random effects logistic regression was used to compute odds ratios (OR) for the likelihood of guideline adherence controlling for sociodemographic and clinical characteristics, hospital type and region. RESULTS: Multivariate models revealed disparities in use of BCT for women ≤39 years (OR 0.49, 95% CI 0.48-0.50); for Asians (OR 0.67, 95% CI 0.65-0.69); for women in the lowest education quartile (OR 0.89, 95% CI 0.87-0.91); and for women in rural regions, (OR 0.79 95% CI 0.76-0.81). The largest radiotherapy disparity was for the oldest women (OR 0.37, 95%CI 0.37-0.38), and in rural regions OR 0.67, 95% CI 0.63-0.71. Over time, differences persisted in BCT use (for race, income, education, insurance type); and for endocrine therapy (by race and education). CONCLUSION: There was mixed progress in reducing disparities in guideline adherence. These results are conservative, since the most favorable tumor stages were analyzed in the NCDB, which reflects higher quality of care than non-participating hospitals.

Tamoxifen Acceptance and Adherence among Patients with Ductal Carcinoma In Situ (DCIS) Treated in a Multidisciplinary Setting.

Tamoxifen and other endocrine agents have proven benefits for women with ductal carcinoma in situ (DCIS), but low patient acceptance is widely reported. We examined factors associated with tamoxifen acceptance and adherence among DCIS patients who received a recommendation for therapy in a multidisciplinary setting. Using our institutional database, we identified women diagnosed with DCIS, 1998 to 2009, who were offered tamoxifen. We recorded data on demographics, tumor and therapy variables, tamoxifen acceptance, and adherence to therapy for ≥4 years. Univariable and multivariable analyses were conducted using logistic regression to identify factors specific to each group that were related to acceptance and adherence. A total of 555 eligible women identified, of whom 369 were offered tamoxifen; 298 (81%) accepted, among whom 214 (72%) were adherent, 59 of 298 (20%) were nonadherent, and for 25 (8%), adherence was undetermined. After stepwise elimination in adjusted logistic regression models, acceptance of breast radiotherapy was associated with acceptance of tamoxifen [OR, 2.22; 95% confidence interval (CI), 1.26-3.90; P < 0.01], as was a medical oncology consultation (OR, 1.76; 95% CI, 0.99-3.15; P = 0.05). Insured patients were more likely to adhere to tamoxifen (OR, 6.03; 95% CI, 2.60-13.98; P < 0.01). The majority of nonadherent women (n = 38/56, 68%) discontinued the drug during the first year of treatment with 48 (86%) citing adverse effect(s) as the reason. In a multidisciplinary, tertiary care setting, we observed relatively high rates of acceptance and adherence of tamoxifen. Acceptance of tamoxifen and radiotherapy were associated, and adherence was influenced by insurance status.Key Message: Tamoxifen acceptance and adherence following resection of DCIS of the breast is related to acceptance of radiotherapy and may be improved by confirmation of the recommendation by a medical oncologist. Despite the low cost of tamoxifen, adherence to therapy is significantly impacted by lack of insurance; those who discontinue therapy report adverse effects as a major reason. Cancer Prev Res; 10(7); 389-97. ©2017 AACR.

Care for a Patient With Cancer As a Project: Management of Complex Task Interdependence in Cancer Care Delivery.

Cancer care is highly complex and suffers from fragmentation and lack of coordination across provider specialties and clinical domains. As a result, patients often find that they must coordinate care on their own. Coordinated delivery teams may address these challenges and improve quality of cancer care. Task interdependence is a core principle of rigorous teamwork and is essential to addressing the complexity of cancer care, which is highly interdependent across specialties and modalities. We examined challenges faced by a patient with early-stage breast cancer that resulted from difficulties in understanding and managing task interdependence across clinical domains involved in this patient's care. We used team science supported by the project management discipline to discuss how various task interdependence aspects can be recognized, deliberately designed, and systematically managed to prevent care breakdowns. This case highlights how effective task interdependence management facilitated by project management methods could markedly improve the course of a patient's care. This work informs efforts of cancer centers and practices to redesign cancer care delivery through innovative, practical, and patient-centered approaches to management of task interdependence in cancer care. Future patient-reported outcomes research will help to determine optimal ways to engage patients, including those who are medically underserved, in managing task interdependence in their own care.

Gene Methylation and Cytological Atypia in Random Fine-Needle Aspirates for Assessment of Breast Cancer Risk.

Methods to determine individualized breast cancer risk lack sufficient sensitivity to select women most likely to benefit from preventive strategies. Alterations in DNA methylation occur early in breast cancer. We hypothesized that cancer-specific methylation markers could enhance breast cancer risk assessment. We evaluated 380 women without a history of breast cancer. We determined their menopausal status or menstrual cycle phase, risk of developing breast cancer (Gail model), and breast density and obtained random fine-needle aspiration (rFNA) samples for assessment of cytopathology and cumulative methylation index (CMI). Eight methylated gene markers were identified through whole-genome methylation analysis and included novel and previously established breast cancer detection genes. We performed correlative and multivariate linear regression analyses to evaluate DNA methylation of a gene panel as a function of clinical factors associated with breast cancer risk. CMI and individual gene methylation were independent of age, menopausal status or menstrual phase, lifetime Gail risk score, and breast density. CMI and individual gene methylation for the eight genes increased significantly (P < 0.001) with increasing cytological atypia. The findings were verified with multivariate analyses correcting for age, log (Gail), log (percent density), rFNA cell number, and body mass index. Our results demonstrate a significant association between cytological atypia and high CMI, which does not vary with menstrual phase or menopause and is independent of Gail risk and mammographic density. Thus, CMI is an excellent candidate breast cancer risk biomarker, warranting larger prospective studies to establish its utility for cancer risk assessment. Cancer Prev Res; 9(8); 673-82. ©2016 AACR.

A Pilot Assessment of Ethnic Differences in Cosmetic Outcomes following Breast Conservation Therapy.

BACKGROUND: One of the primary benefits of breast conserving therapy (BCT) is the potential ability to preserve the aesthetic appearance of the breast. However, current literature and clinical experience suggest that the aesthetic benefits of BCT may not be equally shared among ethnic groups. This is a pilot study that uses novel techniques to evaluate the cosmetic outcomes of African American and white women following BCT. METHODS: A total of 21 participants (10 African American and 11 white) completed the study. Cosmetic outcomes following BCT were evaluated by a multidisciplinary team using both quantitative and qualitative measures, including 3-dimensional photographic analysis and a pilot questionnaire. Preliminary measures were taken to evaluate the validity of the questionnaire. RESULTS: There were no statistically significant differences in objective measures of breast symmetry between African American patients and white patients (P > 0.05 in all cases). However, all raters reported the African American patients to have worse breast symmetry and appearance when compared with white patients. Interrater reliability was found to be fair with regard to the nipple complex questions [intraclass correlation (ICC), 0.56], good with regard to the breast mound questions (ICC, 0.66), and poor with regard to the scar appearance questions (ICC = 0.32). CONCLUSIONS: Although generalizing the results of this study is limited by the small sample size, it seems that there is a difference in the perception of cosmetic outcomes between white and African American patients. The novel techniques of cosmetic evaluation used in this study show promise toward identifying variables that can affect cosmetic outcome following BCT.

Individualized risk of surgical-site infection: an application of the breast reconstruction risk assessment score.

BACKGROUND: Risk factors for surgical-site infection following beast reconstruction have been thoroughly investigated at a population level. However, traditional population-based measures may not always capture the nuances of individual patients. The authors aimed to develop a validated breast reconstruction risk assessment calculator for surgical-site infection that informs risk at an individual level. METHODS: Mastectomies with immediate reconstruction (n = 16,069) from 2005 to 2011 were identified from the National Surgical Quality Improvement Program database. A multiple logistic regression model was created for postoperative surgical-site infection. Hosmer-Lemeshow, C statistic, and Brier score were computed to assess model performance. Bootstrap analysis validated the model. RESULTS: A robust, validated risk model for surgical-site infection was developed using 11 covariates. The model Hosmer-Lemeshow p value was 0.371, the Brier score was 0.0357, and the C statistic was 0.682 (optimism-corrected C statistic, 0.678). The distribution of individual risks demonstrated a positive skew. Population-derived risk underestimated or overestimated individual risk by at least 1.5-fold in nearly one-fifth of all patients. CONCLUSIONS: The breast reconstruction risk assessment score risk calculator for surgical-site infection mitigates the potentially inaccurate interpolation of population-based risk to individual patients. The authors concomitantly developed an online interface-accessible by patients and surgeons alike-to quantify a patient's risk for surgical-site infection, better informing evidence-based decisions and managing patient expectations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Breast ductal lavage for assessment of breast cancer biomarkers.

Lavage of the ductal systems of the breast provides fluid (DLF) containing hormones and products of hormone actions that may represent more accurately the composition of the breast than samples collected from blood or urine. The present study was undertaken to assess the presence of potential cancer biomarkers, their variation among individuals at high risk for breast cancer, and differences associated with menopause and tamoxifen treatment. Seventy seven tamoxifen-eligible subjects with a 5-year breast cancer risk estimate (Gail > 1.6%)(N = 53) or recently diagnosed breast cancer (N = 24) were offered tamoxifen therapy; those not accepting tamoxifen were under observation only. After six months, all subjects underwent ductal lavage (DL) in an unaffected breast. Estradiol (E2), estrone sulfate, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate, progesterone, cathepsin D and epidermal growth factor (EGF) were measured in DLF by immunoassays. Data were expressed as the mass of analyte per mg of protein in DLF and normalized by natural log transformation. With the exception of DHEA, none of the analytes measured were significantly lower in postmenopausal women than in premenopausal women. The mean log(e) concentration difference in estradiol was 10.9%. Tamoxifen treatment for 6 months did not result in a significantly greater concentration of E2 or in any of the other analytes in DLF of pre- or postmenopausal women. The between-duct variance of the concentration of free steroids within the same breast averaged 51% less than that between subjects, and was similar to that of non-diffusible proteins. The maintenance of estradiol concentrations in the breast after menopause demonstrates the importance of local biosynthesis. The fact that DLF E2 does not reflect the high serum concentrations of E2 during tamoxifen treatment indicates that breast concentrations of estradiol may be under feedback control. Unlike studies of low risk populations, progesterone concentrations were not significantly less in postmenopausal than in premenopausal women. The similarity in variance of free steroids and protein analytes between ducts of a breast indicates little transfer of steroids between lobules.