Citations

Abstract Identifying risk factors for women at high risk of symptom-detected breast cancers that were missed by screening would enable targeting of alternative prevention strategies. To identify breast cancer risk factors by mode of detection, we examined these associations in heavily-screened women from the Cancer Prevention Study (CPS)-II Nutrition Cohort. Among 76,406 women followed for a median of 13.8 years, 2,469 screen-detected and 1,189 symptom-detected breast cancer cases were diagnosed. Multivariable-adjusted associations were estimated using joint Cox proportional hazards regression models with person-time calculated contingent on screening. The mean (standard deviation) age at baseline was 62.0 (6.6) years for non-cases, 61.6 (6.1) for screen-detected cases, and 61.5 (6.2) for symptom-detected cases. Women with symptom-detected tumors were diagnosed at a slightly younger age (mean=69.4) and less likely to be diagnosed with a localized tumor (65.3%), than women with a screen-detected tumor (mean age at diagnosis=70.4 and localized tumors=83.3%). Factors associated with higher risks of symptom detected vs. screen detected breast cancer, included: current combined menopausal hormone use (HR=2.04, 95% CI 1.70 - 2.46 vs. HR=1.43, 95% CI 1.25 - 1.63), current estrogen only menopausal hormone use (HR=1.41, 95% CI 1.15 - 1.72 vs. HR=0.94, 95% CI 0.82 - 1.09), and history of benign breast disease (HR=1.89, 95% CI 1.67 - 2.13 vs. HR=1.49, 95% CI 1.36 - 1.62). The opposite pattern of higher risk of screen detected vs. symptom detected breast cancer was observed for greater adult weight gain (HR=2.32, 95% CI 1.91 - 2.82 vs. HR=1.42, 95% CI 1.10 - 1.84) and alcohol intake (HR=1.39, 95% CI 1.24 - 1.64 vs. HR=1.20, 95% CI 0.92 - 1.58). Our results suggest that understanding risk factors for symptom-detected cancers may help identify women who would benefit from more intensive screening to facilitate early detection. Citation Format: Mia M. Gaudet, Emily Deubler, W. Ryan Diver, Samantha Puvanesarajah, Alpa V. Patel, Ted Gansler, Dana Flanders, Mark Sherman, Susan Gapstur. Breast cancer risk factors by mode of detection among screened women in the Cancer Prevention Study-II [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4211.

Abstract Treatment of estrogen receptor positive (ER+) breast cancer have included single-agent endocrine therapy, such as with aromatase inhibitors (AIs) and, more recently, AIs in combination with the cyclin-dependent kinase 4/6 inhibitor palbociclib. While combination therapy is effective, drug resistance is a well-known phenomenon and breast cancer cells can acquire resistance to aromatase inhibitor and palbociclib individually. In anticipation of patient who may become resistant to combination therapy with aromatase inhibitor (letrozole) and palbociclib, this current study has 1) developed MCF7Ca cells resistant to both letrozole and palbociclib (MCF7Calet+palb); 2) characterized them in comparison to drug naïve (MCF7Ca) and letrozole alone-resistant (LTLTCa) cells; and 3) explored potential treatments. Characterization of MCF7Calet+palb cells by phase contrast microscopy, mammosphere assays, and invasion assays, indicate that they have more basal/mesenchymal morphology, produce more mammospheres (an indicator of cancer stem cells; 150±10 vs. 80±10 in MCF7Ca and 123± 8 in LTLTCa cells), and are more invasive (1200±50 cells vs. 791±15 in MCF7Ca cells). The more aggressive phenotype of MC7Calet+palb correlated with changes in protein expression. Compared to the other cell lines, MCF7Calet+palb expressed significantly lower fold expression levels of cell cycle cyclin D1 (0.2±0.1), phosphorylated CDK9 (0.5±0.1), and phosphoRb and total Rb (0.4±0.2), but higher levels of phosphoCDK1 and CDK2 (1.4±0.1 and 3.1±0.6). Regarding growth pathway proteins, MCF7Calet+palb comparably had increased HER2 and phosphorylated Akt (6.2±1.3 and 3.3±1.2, resp.) as LTLTCa vs. MCF7Ca cells, but had even more reduced levels of ERα (0.04 vs. 0.1±0.4 in LTLTCa and 1±0.01 in MCF7Ca). Cancer stem cell marker breast cancer resistance protein (BCRP) was increased further in MCF7Calet+palb cells (2.11-fold). Based on these results, the effect of dinaciclib, a broader range CDK inhibitor, was studied. In MTT assays, dinaciclib was shown to be effective in inhibiting cell viability in all three cell types. Dinaclicib’s IC50s were 1.4 nM (MC7Ca) 9.5 nM (LTLTCa) and 12.4 nM in MCF7Calet+palb cells, while palbociclib IC50s were 1.5 μM, 11.2 μM, and 118 μM, respectively. Dinaciclib also significantly reduced mammosphere formation 0.01-fold and cell invasion/migration by 0.3-fold vs. untreated. Lastly, preliminary exome sequencing data suggested highly mutated FGFRL1, ARL11, and FCGBP genes, among others, when MCF7Calet+palb cells were compared to MCF7Ca cells. Overall, these results suggest that acquired resistance to combination therapy with letrozole and palbociclib induces genetic, molecular, and phenotypic changes in breast cancer cells, and that dinaciclib may be an effective treatment to either treat and/or prevent this resistance. Citation Format: Armina Kazi, Emily Shukdinas, Saranya Chumsri, Gauri J. Sabnis. Characterization of breast cancer cells resistant to letrozole and palbociclib combination therapy and the potential of dinaciclib to treat such resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1014.

AbstractContrary to common perception, modern palliative care (PC) is applicable to all people with an incurable disease, not only cancer. PC is appropriate at every stage of disease progression, when PC needs emerge. These needs can be of physical, emotional, social, or spiritual nature. This document encourages the use of validated assessment tools to recognize such needs and ascertain efficacy of management. PC interventions should be provided alongside cardiologic management. Treating breathlessness is more effective, when cardiologic management is supported by PC interventions. Treating other symptoms like pain or depression requires predominantly PC interventions. Advance Care Planning aims to ensure that the future treatment and care the person receives is concordant with their personal values and goals, even after losing decision-making capacity. It should include also disease specific aspects, such as modification of implantable device activity at the end of life. The Whole Person Care concept describes the inseparability of the physical, emotional, and spiritual dimensions of the human being. Addressing psychological and spiritual needs, together with medical treatment, maintains personal integrity and promotes emotional healing. Most PC concerns can be addressed by the usual care team, supported by a PC specialist if needed. During dying, the persons’ needs may change dynamically and intensive PC is often required. Following the death of a person, bereavement services benefit loved ones. The authors conclude that the inclusion of PC within the regular clinical framework for people with heart failure results in a substantial improvement in quality of life as well as comfort and dignity whilst dying.

AbstractThe purpose of this case‐matched study was to determine how frequently fibromyalgia is associated with different paroxysmal neurological disorders and explore the utility of fibromyalgia as a predictor for the diagnosis of psychogenic non‐epileptic seizures. The billing diagnosis codes of 1,730 new, non‐selected patient encounters were reviewed over a three‐year period for an epileptologist in a neurology clinic to identify all patients with historical diagnoses of fibromyalgia. The frequency with which epileptic seizures, psychogenic non‐epileptic seizures, and physiological non‐epileptic events were comorbid with fibromyalgia was assessed. Age and gender case‐matched controls were used for a between‐group comparison. Wilcoxon tests were used to analyse interval data, and Chi‐square was used to analyse categorical data (p<0.05). Fibromyalgia was retrospectively identified in 95/1,730 (5.5%) patients in this cohort. Females represented 95% of the fibromyalgia sample (age: 53 years; 95% CI: 57, 51). Forty‐three percent of those with fibromyalgia had a non‐paroxysmal, neurological primary clinical diagnosis, most commonly chronic pain. Paroxysmal events were present in 57% of fibromyalgia patients and 54% of case‐matched controls. Among patients with fibromyalgia and paroxysmal disorders, 11% had epileptic seizures, 74% had psychogenic non‐epileptic seizures, and 15% had physiological non‐epileptic events, compared to case‐matched controls with 37% epileptic seizures, 51% psychogenic non‐epileptic events, and 12% physiological non‐epileptic events (p = 0.009). Fibromyalgia was shown to be a predictor for the diagnosis of psychogenic non‐epileptic seizures in patients with undifferentiated paroxysmal spells. However, our results suggest that the specificity and sensitivity of fibromyalgia as a marker for psychogenic non‐epileptic seizures in a mixed general neurological population of patients is less than previously described.

Abstract Heterozygous loss-of-function mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A). PGRN is a highly conserved, secreted glycoprotein and functions in the central nervous system as a key modulator of microglial function. Hence, altered microglial function caused by PGRN deficiency may be tied to the pathogenesis of FTLD-TDP. Our previous studies showed that haploinsufficiency of GRN mutations extends to microglial PGRN expression in the hippocampal CA1 region. In this study, we found that the CA1 sector was associated with less neuronal loss and more frequent TDP-43 inclusions in FTLD-TDP type A cases with GRN mutations than in sporadic cases. In addition, the CA1 region in GRN mutation cases contained more rod-like microglia, which also had reduced PGRN expression. These findings suggest that the profile of TDP-43 inclusions, neuronal number, and microgliosis in the CA1 sector of FTLD-TDP type A cases may be influenced by GRN gene expression status.

AbstractBackgroundGlioblastoma (GBM) represents an aggressive cancer type with a median survival of only 14 months. With fewer than 5% of patients surviving 5 years, comprehensive profiling of these rare patients could elucidate prognostic biomarkers that may confer better patient outcomes. We utilized multiple molecular approaches to characterize the largest patient cohort of isocitrate dehydrogenase (IDH)–wildtype GBM long-term survivors (LTS) to date.MethodsRetrospective analysis was performed on 49 archived formalin-fixed paraffin embedded tumor specimens from patients diagnosed with GBM at the Mayo Clinic between December 1995 and September 2013. These patient samples were subdivided into 2 groups based on survival (12 LTS, 37 short-term survivors [STS]) and subsequently examined by mutation sequencing, copy number analysis, methylation profiling, and gene expression.ResultsOf the 49 patients analyzed in this study, LTS were younger at diagnosis (P = 0.016), more likely to be female (P = 0.048), and MGMT promoter methylated (UniD, P = 0.01). IDH-wildtype STS and LTS demonstrated classic GBM mutations and copy number changes. Pathway analysis of differentially expressed genes showed LTS enrichment for sphingomyelin metabolism, which has been linked to decreased GBM growth, invasion, and angiogenesis. STS were enriched for DNA repair and cell cycle control networks.ConclusionsWhile our findings largely report remarkable similarity between these LTS and more typical STS, unique attributes were observed in regard to altered gene expression and pathway enrichment. These attributes may be valuable prognostic markers and are worth further examination. Importantly, this study also underscores the limitations of existing biomarkers and classification methods in predicting patient prognosis.

PURPOSE This pilot study examined the ability to operationalize the collection of real-world data to explore the potential use of real-world end points extracted from data from diverse health care data organizations and to assess how these relate to similar end points in clinical trials for immunotherapy-treated advanced non–small-cell lung cancer. PATIENTS AND METHODS Researchers from six organizations followed a common protocol using data from administrative claims and electronic health records to assess real-world end points, including overall survival (rwOS), time to next treatment, time to treatment discontinuation (rwTTD), time to progression, and progression-free survival, among patients with advanced non–small-cell lung cancer treated with programmed death 1/programmed death-ligand 1 inhibitors in real-world settings. Data sets included from 269 to 6,924 patients who were treated between January 2011 and October 2017. Results from contributors were anonymized. RESULTS Correlations between real-world intermediate end points (rwTTD and time to next treatment) and rwOS were moderate to high (range, 0.6 to 0.9). rwTTD was the most consistent end points as treatment detail was available in all data sets. rwOS at 1 year post–programmed death-ligand 1 initiation ranged from 40% to 57%. In addition, rwOS as assessed via electronic health records and claims data fell within the range of median OS values observed in relevant clinical trials. Data sources had been used extensively for research with ongoing data curation to assure accuracy and practical completeness before the initiation of this research. CONCLUSION These findings demonstrate that real-world end points are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision making. Differences observed likely reflect true differences between real-world and protocol-driven practices.