bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation fidelity, attitudes, and influence: a novel approach to classifying implementer behavior
Authors: Swindle Taren , Rutledge Julie M. , Martin Janna , Curran Geoffrey M.
Published: June 2022

Background

The current study sought to (1) describe a new classification approach for types of implementer behavior and (2) explore the implementer behavior change in response to tailored implementation facilitation based on the classifications.

Methods

A small-scale, cluster-randomized hybrid type III implementation trial was conducted in 38 early care and education classrooms that were part of the Together, We Inspire Smart Eating (WISE) program. WISE focuses on 4 evidence-based practices (EBPs), which are implemented by teachers to promote nutrition. External facilitators (N = 3) used a modified Rapid Assessment Procedure Informed Clinical Ethnography (RAPICE) to complete immersion (i.e., observations) and thematic content analyses of interviews to identify the characteristics of teachers’ behavior at varying levels of implementation fidelity. Three key factors—attitudes toward the innovation, fidelity/adaptations, and influence—were identified that the research team used to classify teachers’ implementation behavior. This process resulted in a novel classification approach. To assess the reliability of applying the classification approach, we assessed the percent agreement between the facilitators. Based on the teachers’ classification, the research team developed a tailored facilitation response. To explore behavior change related to the tailored facilitation, change in fidelity and classification across the school year were evaluated.

Results

The classifications include (1) enthusiastic adopters (positive attitude, meeting fidelity targets, active influence), (2) over-adapting adopters (positive attitude, not meeting fidelity targets, active influence), (3) passive non-adopters (negative attitude, not meeting fidelity targets, passive influence), and (4) active non-adopters (negative attitudes, not meeting fidelity targets, active influence). The average percent agreement among the three facilitators for classification was 75%. Qualitative data support distinct patterns of perceptions across the classifications. A positive shift in classification was observed for 67% of cases between the mid-point and final classification. Finally, we generated an expanded classification approach to consider additional combinations of the three factors beyond those observed in this study.

Conclusions

Data from this study support the ability to apply the classification approach with moderate to high reliability and to use the approach to tailor facilitation toward improved implementation. Findings suggest the potential of our approach for wider application and potential to improve tailoring of implementation strategies such as facilitation.
Molecular characterization and pathogenicity of Mycoplasma capricolum subsp. capricpolum from goats in Morocco
Authors: Semmate Noha , Zouagui Zaid , Elkarhat Zouhair , Bamouh Zahra , Fellahi Siham , Tligui Noursaid , Boumart Zineb , Fihri Ouafaa Fassi , El Harrak Mehdi
Published: June 2022

Mycoplasma capricolum subsp. capricolum (Mcc) is an important etiological agent of contagious agalactia (CA). CA affects small ruminants and is characterized by inducing mastitis, arthritis, kerato-conjunctivitis and respiratory symptoms. The aim of this study was to isolate and characterize Mcc from Moroccan goats with contagious agalactia. A total of 300 Alpine goats were monitored. Serology analysis, molecular identification, and isolation of Mcc were realized from suspected goats. An experimental study was conducted for isolated Mcc to determine their pathogenicity. Thus, clinical observation showed that respiratory symptoms were predominant in young animals, and other symptoms, such as mastitis, keratoconjunctivitis and lameness, were more frequently detected in adult goats. Of the 80 tested blood samples, 28 sera were seropositive for Mcc antibodies. Mcc was identified by polymerase chain reaction (PCR) in milk, lung tissue and synovial liquid samples. The isolation of Mcc was successful through bacterial culture from lung tissue. LppA gene sequence of this strain revealed 98.1% similarity with the reference strain (ATCC 27343), with 11 missense variants. Experimental infection resulted in severe and generalized CA disease in sheep and goats, confirming the high pathogenicity of the Moroccan Mcc isolate.
The 35th annual advances in contrast ultrasound international bubble conference, Chicago 2021: synopsis and take-home messages
Authors: Dunleavy Michael , Goldberg Alan , Feinstein Steven , Wilson Stephanie , Mulvagh Sharon , Nihoyannopoulos Petros
Published: June 2022

The 35th Annual Advances in Contrast Ultrasound International Bubble Conference convened in Chicago, IL, USA, on September 30th to October 1st, 2021. It featured a range of novel research from animal studies to clinical applications in multiple organ systems, demonstrating the utility of contrast enhanced ultrasound (CEUS). A multidisciplinary group of experts on the use of CEUS, including physicians, basic scientists, engineers, and industry partners, convened to discuss cutting edge research and new applications for CEUS. The conference demonstrated the wide range of CEUS uses and potential uses, including cardiac risk stratification, sonothrombolysis, peripheral vascular reperfusion, liver and renal mass evaluation, lymphatic evaluation, sentinel node identification, and CEUS use in pediatrics. The International Contrast Ultrasound Society uses this information to continue advocating for the safe and appropriate use of CEUS.
Poverty, race, ethnicity, and survival among U.S. children with non-metastatic osteosarcoma treated on EURAMOS-1: A report from the Children’s Oncology Group.
Authors: Ilcisin Lenka Anne Skaidrite , Han Ruxu , Krailo Mark D. , Gorlick Richard Greg , Nadel Helen Ruth , Binitie Odion , Janeway Katherine A. , Bona Kira
Published: June 2022

10004

Background: Children living in poverty and those who identify as a race/ethnicity other than non-Hispanic White experience higher rates of relapse and lower overall survival across many pediatric cancers. Racial, ethnic and socioeconomic disparities have not been comprehensively investigated in osteosarcoma. We leveraged data from US-enrolled patients on the recent international EURAMOS-1 trial to investigate disparities in survival outcomes. Aim: Identify if race/ethnicity, household or neighborhood poverty exposure are associated with event-free survival (EFS) or overall survival (OS) in patients with non-metastatic osteosarcoma enrolled at a US-center on EURAMOS-1. Methods: Retrospective cohort study of US patients aged 5-21 years enrolled on EURAMOS-1 with a diagnosis of non-metastatic, primary osteosarcoma. Poverty was the primary exposure defined at the household- (sole coverage with Medicaid or CHIP public insurance versus other) and neighborhood- (Census-defined high-poverty ZIP code with >20% of residents living at <100% Federal Poverty Level vs other) levels. Race and ethnicity were categorized to reflect structural inequities and historically marginalized populations, as Hispanic, non-Hispanic Black (NHB), non-Hispanic Other (NHO), and non-Hispanic White (NHW). OS and EFS as a function of time from trial enrollment were estimated using the Kaplan-Meier method. Hypotheses of associations between risks for EFS-event, death and post-relapse death with poverty-exposures and race/ethnicity were assessed using log-rank tests. Statistical comparisons were performed excluding patients with missing values for the exposures considered. P-values <=0.05 were considered significant. Results: Among 758 patients, 27% were household poverty-exposed and 29% were neighborhood-poverty exposed. Twenty-one percent of children identified as Hispanic, 17% NHB, 5% NHO and 57% NHW. Neither household- or neighborhood-poverty, nor race/ethnicity were significantly associated with risks for EFS-event or death. Post-relapse risk for death differed significantly across race/ethnicity with NHB at greatest risk compared to others (4-Year post-relapse survival 35.7% Hispanic vs. 13.0% NHB vs. 43.8% NHO vs 38.9% NHW; p=0.0046). Conclusions: Neither poverty-exposures nor race/ethnicity were associated with EFS or OS in this COG trial-enrolled cohort, suggesting equitable outcomes following standardized therapy. Despite this, non-Hispanic Black children experienced significantly inferior post-relapse survival. Investigation of mechanisms driving these post-relapse disparities, including inequities in health care delivery and access to post-relapse trial-enrollment, are paramount to ensure equity in outcomes for all children with cancer.
Benefits, harms, and burden of colorectal cancer screening among childhood cancer survivors previously treated with abdominal-pelvic radiation.
Authors: Yeh Jennifer M , Seguin Claudia L. , Whitton Jillian , Leisenring Wendy M. , Armstrong Gregory T. , Henderson Tara O. , Hudson Melissa M. , Nathan Paul C. , Neglia Joseph Philip , Oeffinger Kevin C. , Diller Lisa , Knudsen Amy B
Published: June 2022

10015

Background: Survivors of childhood cancer treated with abdominal-pelvic radiation are at increased risk for colorectal cancer (CRC). The Children’s Oncology Group recommends early initiation of CRC screening at age 30, yet the benefits and burden are unknown. Methods: We used incidence and mortality data from the Childhood Cancer Survivor Study to modify the SimCRC model from the Cancer Intervention and Surveillance Modeling Network (CISNET) to reflect high CRC and competing mortality risks among survivors, assuming the elevated cancer risk arises from higher adenoma onset. Strategies evaluated varied by modality (no screening, colonoscopy, multitarget stool DNA [mtsDNA] testing, fecal immunochemical testing [FIT]), screening start age (25, 30, 35, 40, 45) and screening interval (every 3, 5 or 10 yrs for colonoscopy; every 1, 2 or 3 yrs for mtsDNA and FIT). Abnormal stool test results were followed up with colonoscopy. Screening performance and complication rates were based on published studies. Analyses assumed full uptake and adherence to all screening and follow-up procedures. To identify the optimal strategy for each modality, we estimated the number of colonoscopies required per additional life-year gained and compared it to benchmarks for screening strategies recommended by the US Preventive Services Task Force for average-risk individuals. Results: Among a simulated cohort of 20-yr-old 5-yr survivors with a history of abdominal-pelvic radiation, the cumulative CRC risk at age 50 was 0.8%, approximately twice that predicted among general population average-risk individuals (0.4%). In the absence of screening, 73 per 1000 survivors would be diagnosed with CRC in their lifetime and 29 would die from the disease. All screening strategies evaluated were estimated to yield substantial reductions in the lifetime number of CRC cases (45-71 cases averted per 1000) and deaths (23-28 deaths averted per 1000). The estimated lifetime number of colonoscopies ranged from 1781 to 14,625 per 1000. The lifetime number of colonoscopy complications was relatively low at 9 to 20 per 1000. Based on the burden-to-benefit ratios, colonoscopy every 10 yrs starting at age 30, mtsDNA every 3 yrs starting at age 30, or FIT every 3 yrs starting at age 25 were the optimal screening strategies identified (Table). Conclusions: Early initiation of screening may substantially reduce CRC mortality among high-risk childhood cancer survivors. These estimates of the balance of screening benefits and burden can inform follow-up care guidelines. [Table: see text]
Identifying trends for high symptom burden across the care continuum in adolescents and young adults (AYA) with hematologic malignancies.
Authors: Monick Sarah Elizabeth , Hanson Collin , Wang Amy Yuan , Lee Sang Mee , Hoehn Karen Sarah , Hlubocky Fay J. , Stock Wendy , Duvall Adam , McNeer Jennifer Lynn , Henderson Tara O. , Daugherty Christopher
Published: June 2022

10019

Background: Cancer in adolescence and young adulthood is a non-normative life event associated with profound long-term physical and psychosocial consequences. Prior studies specifically demonstrate AYA patients with hematologic malignancies experience high symptom burden with poor quality of life. Here, we describe trends and factors associated with high symptom burden in patients treated at a multi-disciplinary AYA leukemia clinic at an academic medical center. Methods: The Edmonton Symptom Assessment Scale [ESAS] (measuring physical symptoms) and Brief Symptom Inventory-18 [BSI-18] (measuring psychological distress) were administered at baseline, 3 months, and 6 months from initial survey. Baseline demographic and treatment characteristics were collected. All patients had leukemia or lymphoma, were on treatment or in survivorship, and had access to a palliative care provider who was integrated into the clinic. Data was analyzed using Wilcox ranked sum test and linear mixed-effects model testing. Results: Of the 31 patients (median age 29 years, range 18-43) who completed surveys, 25 (80%) completed surveys at 6 months; 48% were female, 58% were white, 16% lived alone, 28% were single, 37% had children, 54% completed college, and 35% had an annual household income ≥ $75,000. Phases of care included 52% on intensive frontline/salvage treatment, 19% in maintenance (i.e. lower intensity) therapy, 16% as recent stem cell transplant (SCT) recipients (< 1 year since date of transplant), and 13% in survivorship. Overall, ESAS scores among patients were similar regardless of care phases; however, patients on frontline/salvage therapy reported higher fatigue than those in maintenance (p = 0.01). Moderate-severe symptoms (defined as ESAS > 3), including tiredness, anxiety, poor appetite, and poor feeling of well-being, were reported regardless of phase of care. At 6 months, there was no significant change in BSI-18 scores compared to baseline, while tiredness (p = 0.02), depression (p = 0.01), and constipation (p = 0.02) improved; no ESAS scores worsened. Age ≥ 30 was associated with worsening anxiety (p = 0.01) at 6 months vs baseline, while no statistically significant differences in ESAS scores were observed among race, education, relationship status, presence of children, living arrangement, or income. Conclusions: AYA patients with hematologic malignancies experience high symptom burden independent of demographic characteristics or phase of care. These findings highlight the need for standard symptom screening at each visit and the importance of incorporating supportive care throughout the continuum.
Predictors of differential outcomes according to response to induction chemotherapy in high-risk neuroblastoma.
Authors: Sokol Elizabeth , LaBarre Brian , Naranjo Arlene , Pinto Navin R. , Kreissman Susan G. , Granger Meaghan , Park Julie R. , Bagatell Rochelle , DuBois Steven G.
Published: June 2022

10032

Background: Response to induction chemotherapy has been shown to predict outcome in patients with high risk neuroblastoma, with those achieving a complete response (CR) having superior outcomes. Little is known about what factors impact survival within groups of patients with favorable and unfavorable end-induction response. We evaluated whether conventional prognostic factors remain prognostic in subsets of patients defined by response to induction. Methods: Patients from four COG high risk trials (A3973, ANBL02P1, ANBL0532, and ANBL12P1) were included. End-induction response was determined according to the 1993 International Neuroblastoma Response Criteria (INRC). Patients were categorized as having end-induction responses of CR, partial response (PR) or better, less than PR without progressive disease (PD), and PD. Univariate Cox models calculated OS hazard ratios for clinical and biological variables in subsets defined by response category. Results: 1,244 patients were included. Among all patients, age >5 years, INSS stage 4 disease, adrenal primary site and unfavorable histology by INPC were associated with inferior OS (see Table). Among patients who achieved a CR, stage 4 disease was the only factor that remained significantly associated with worse OS. Among those who achieved PR or better, age >5 years, stage 4 disease and unfavorable histology remained significantly associated with inferior OS. For those with less than PR but without PD, adrenal primary site, MYCN amplification and 1p LOH were significantly associated with inferior OS. For those with PD, MYCN amplification and 1p LOH were associated with worse OS, but older age was associated with better OS. Conclusions: Specific prognostic factors in neuroblastoma are associated with differential survival in groups defined by response to induction. Age, stage, and histology appear to be associated with OS for patients with more favorable response to induction, whereas MYCN and 1p LOH play a greater role in patients with unfavorable response to induction. These data can help to further define prognosis for patients with variable responses to induction. [Table: see text]
Predicting outcomes with circulating adrenergic neuroblastoma mRNAs in children with relapsed and refractory neuroblastoma: A BEACON-Neuroblastoma biomarker study.
Authors: Moreno Lucas , Weston Rebekah , Viprey Virginie , Tchirkov Andrei , Corrias Maria , Lammens Tim , Gray Juliet , Owens Cormac , Laidler Jennifer , Gambart Marion , Castel Victoria , Van Eijkelenburg Natasha , Nysom Karsten , Laureys Genevieve , Castellano Aurora , Gerber Nicolas U. , Ladenstein Ruth Lydia , Valteau Couanet Dominique , Wheatley Keith , Burchill Susan A
Published: June 2022

10039

Background: Children with relapsed and refractory neuroblastoma (RR-NBL) have poor outcomes. Early identification of children at greatest risk of relapse could mean timelier modifications of treatment to improve outcomes. High levels of adrenergic neuroblastoma mRNAs in blood of children with stage M neuroblastoma receiving frontline treatment predict poor outcome (Viprey PMID: 24590653). Since these markers have not been thoroughly studied in the RR-NBL population, we have prospectively evaluated the prognostic potential of the adrenergic neuroblastoma mRNAs paired-like homeobox 2B (PHOX2B ) and tyrosine hydroxylase (TH) in blood from children with RR-NBL treated in the BEACON-Neuroblastoma trial (NCT02308527). Methods: Blood samples collected at baseline from 88 children were analysed by reverse transcriptase polymerase chain reaction (RTqPCR) for PHOX2B and TH mRNAs. The prognostic power of these mRNAs was evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression. Progression-free (PFS) and overall survival (OS) were calculated from the date that the blood sample was taken at screening to the date of an event; progression, disease recurrence, death or censored alive at the last clinical evaluation. Results: Of the children in this cohort, 58 (66%) had relapsed and 30 (34%) had refractory disease. Twenty-three (26%) had MYC-N amplified tumours. TH and PHOX2B mRNAs were detected in 55% and 60% of blood samples respectively; the correlation coefficient between TH and PHOX2B was 0.75. Higher levels of TH, PHOX2B mRNAs or both combined were associated with reduced PFS and OS (Table). For TH, median PFS for children with TH levels below the median was 12 months (95%CI, 4.6–13 months) versus 5.5 months (95%CI, 1.8–9.4 months) for those children with TH levels above the median. For PHOX2B, median PFS for children with PHOX2B levels below the median was 11.5 months (95%CI, 7.6–34 months), compared to 5.7 months (95%CI, 1.8–10.5 months) where levels were above the median. Conclusions: TH and PHOX2B mRNAs in blood collected at baseline identify children with refractory or relapsed neuroblastoma at greatest risk of progression or death. In the RR-NBL setting, this simple blood test could be used to stratify treatment strategies. Clinical trial information: NCT02308527. [Table: see text]
Protein, fat, and animal food intakes and premature aging in adult survivors of childhood cancer: St. Jude Lifetime (SJLIFE) cohort.
Authors: Park Yikyung , Williams AnnaLynn , Finch Emily R , Lanctot Jennifer Q. , Jiang Shu , Krull Kevin R. , Armstrong Gregory T. , Hudson Melissa M. , Colditz Graham A. , Robison Leslie L. , Ness Kirsten K.
Published: June 2022

10055

Background: Childhood cancer survivors are a growing population who appear to be at higher risk for premature aging and age-related chronic health conditions than their peers with no history of cancer. Diet affects many hallmarks of aging, such as inflammation, metabolic dysfunctions, and molecular and epigenetic changes, leading to impairment in physical and cognitive functions and premature death. High consumption of animal foods that are high in protein and fat increase risk for many age-related chronic diseases. However, some studies found protein intake was beneficial for physical frailty in elderly and cancer survivors. Methods: Adult survivors (> = 18 years old) of childhood cancer survivors enrolled in the SJLIFE Cohort between 2007 and 2017 completed a 110-item food frequency questionnaire at study entry (n = 3,322). Survivors’ sociodemographic, cancer, cancer treatments, and medical history data were abstracted from medical records. Health conditions self-reported after cancer diagnosis were clinically validated. Premature aging was assessed using the Deficit Accumulation Index (DAI) based on 45 aging-related health conditions. DAI is categorized into low (< 0.2), medium (0.2-0.34) and high (> 0.35) aging risk groups. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multinomial logistic regressions adjusting for potential confounders. Results: The average age of survivors at baseline was 31 years. Approximately half of the survivors were women, and 82% were white, non-Hispanic. 20% and 8% of survivors were at medium and high risk for aging, respectively. Survivors at high risk for aging tended to be female, smokers, have low socioeconomic status, and received radiation therapy to head and neck, chest, spine or abdomen compared to those at low aging risk. Higher protein intake was associated with a less risk of premature aging (OR = 0.74, 95% CI: 0.58-0.95 for high aging risk group; OR = 0.91, 95% CI: 0.78-1.07 for medium aging risk group, per increment of 5% of total energy intake). On the other hand, higher fat intake was related to an increased risk of premature aging (OR = 1.14, 95% CI: 1.01-1.29 for high aging risk group; OR = 0.99, 95% CI: 0.91-1.08 for medium aging risk group, per increment of 5% of total energy intake). However, substituting monounsaturated fat for other types of fat was associated with a lower risk of premature aging (OR = 0.81 95% CI: 0.70-0.95 for high aging risk group). Red meat (OR = 1.11, 95% CI: 0.87-1.42 for high aging risk group) and dairy intake (OR = 0.99, 95% CI: 0.72-1.38 for high aging risk group) was not related to risk of premature aging. Conclusions: Consuming protein and fat from healthy foods may lower the risk of premature aging in childhood cancer survivors.
Survival in patients with breast cancer and history of autoimmune disease.
Authors: Dedousis Demitrios , Zhang Annie , Vassiliou Anastasia , Cao Shufen , Yammani Deepthi , Kyasaram Ravi Kumar , Shanahan John , Keinath Melissa C. , Hsu Melinda Laine , Fu Pingfu , Dowlati Afshin , Montero Alberto J.
Published: June 2022

1020

Background: Patients with autoimmune disease, specifically systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren syndrome, are at reduced risk of developing breast cancer compared to those without a prior history of autoimmune disease. Despite this, little is known about the survival of patients with concurrent autoimmune disease and breast cancer. This study compared outcomes in patients with breast cancer with and without autoimmune disease. Methods: This study was a retrospective analysis of patients from SEER-Medicare databases from 2007-2014 with breast cancer. Patients with a history of autoimmune disease were identified using ICD-9 codes. The effects of autoimmune disease on overall survival (OS) and cancer-specific survival (CSS) were estimated using multivariable Cox regression and Gray’s method respectively controlling the effects of age, race and chronic kidney disease (CKD). The cumulative CSS was estimated taking death as a competing risk. Results: The overall prevalence of investigated autoimmune diseases among the 137,324 patients with breast cancer was 26.69%. The most common autoimmune diseases identified were RA (23.35%), psoriasis (2.41%) and SLE (1.12%). In stage IV breast cancer patients the OS and CSS were significantly higher in patients with autoimmune disease (p values < 0.0001), with a median OS of 36 months compared to 30 months in patients without autoimmune disease. After adjusting for the effects of age, race, and CKD, autoimmune disease was still predictive of higher OS (HR: 1.46, 95% CI: 1.37 – 1.57, p < 0.0001) and CSS (HR: 1.39, 95% CI: 1.29 – 1.5, p < 0.0001). Patients with autoimmune disease and stage I-III breast cancer, had lower OS (p < 0.0001, p < 0.0001, and p = 0.026 respectively) compared to patients without autoimmune disease. Conclusions: We found a higher prevalence of RA, Crohn disease, ulcerative colitis, and SLE in patients with breast cancer compared to cohorts of similar age ranges in the general population. History of autoimmune disease resulted in significantly improved OS and CSS in patients with stage IV breast cancer even when controlling for age, race and CKD, in this pre-immunotherapy cohort. These results suggest that that anti-tumor immunity plays an important role in late-stage breast cancer, and could be potentially exploited to improve the effectiveness of immunotherapy. Further research into the relationship between autoimmunity and breast cancer is warranted.
The mutational profile of ER-, PR+, HER2- metastatic breast cancer.
Authors: Fischbach Neal A. , Huang Richard S.P. , Lustberg Maryam B. , Pelletier Maureen , Pusztai Lajos , Sivakumar Smruthy , Sokol Ethan , Ross Jeffrey S. , Levy Mia Alyce
Published: June 2022

1025

Background: ER-PR+Her2- breast cancer is a rare subtype occurring at approximately 1% of all breast carcinomas. Most of these cancers behave in an aggressive fashion with limited benefit from anti estrogen therapy, similar to triple negative breast cancer (TNBC). Better characterization of these tumors is needed for predicting clinical behavior, response to endocrine therapy, and eligibility for clinical trials. Here we sought to evaluate the mutational profile of a well curated set of ER-PR+HER2- metastatic breast cancers and compare to other receptor phenotypes. Methods: 2049 consecutive breast cancers submitted to Foundation Medicine for comprehensive genomic profiling (CGP) were included. ER, PR and HER2 expression were abstracted from submitted pathology reports. Cases without complete ER, PR and HER2 information in pathology reports were excluded. CGP was performed as previously described (Frampton, 2013). Results: Patient ages were similar across subgroups. Generally, ER-PR+HER2- tumors were rare (n = 23, 1.1%) and most similar to TNBC in their genomic profiles. These tumors harbored high rates of TP53 and BRCA1 alterations and low rates of PIK3CA, ESR1, and CDH1 alterations. Genomic loss of heterozygosity (gLOH) was similar in the ER-PR+HER2- and ER+PR+HER2-subtypes (8.18% and 8.66% respectively), and lower than TNBC (17.19%). Notably, a high rate of RB1 alterations were identified in the ER-PR+HER2- patients (13%, 3/23), numerically higher than the other subtypes. EGFR, MET, PTEN, CDKN2A and KRAS alterations were also observed at a higher frequency in ER-PR+Her2- cancers (8.7, 4.2, 39.1, 13.0 and 13.0% respectively) relative to the other subtypes. IO drug biomarkers including MSI, TMB and PD-L1 IHC were similar among the groups. Conclusions: The mutational profile for ER-PR+Her2- metastatic breast cancer more closely resembles TNBC than ER+ breast cancer. These data suggest molecular profiling may be a useful adjunct to optimize treatment strategies for this rare subset of cancers. Based on molecular characteristics, we recommend including ER-PR+Her2- patients in clinical trials for TNBC. Finally, genes including RB1, CKDN2A, PTEN, EGFR and MET are mutated at higher frequency in ER-PR+Her2- cancers than other subsets, suggesting unique biology with potential therapeutic implications. [Table: see text]
A phase II, single-arm, open label, Simon two-stage study of pembrolizumab in patients with metastatic HER2-negative breast cancer: Evaluation of impact of germline variants in APOBEC3B (AUROR).
Authors: Ho Gwo Fuang , Lee Soo-Chin , Lim Joanna , Bustam Anita Zarina , Lim Siew Eng , Saad Marniza , Ow Samuel Guan Wei , Ngoi Natalie , Abdul Satar Nur Fadhlina , Malik Rozita Abdul , Alip Adlinda , Law Kian Boon , Toh Yok Yong , Pan Jia Wern , Teo Soo Hwang
Published: June 2022

1026

Background: A germline deletion in the APOBEC3B cytosine deaminase gene [A3Bdel] occurs more frequently in Asian women (45% heterozygous deletion (hetD) and 15% homozygous deletion (homD)) compared to in Caucasian women (15% hetD and 4% homD). Carriers are more likely to develop breast cancer, and cancers in carriers are more likely to have a hypermutator phenotype (with C > T transitions) and to be immune-enriched. In this clinical trial, we aim to evaluate whether the immune activation increases response to checkpoint immunotherapy. Methods: In this open label, single arm Phase II study of single agent pembrolizumab in metastatic HER2-receptor negative breast cancer patients with germline deletion in A3B, 40 evaluable subjects who have received > = 1 but < = 3 lines of therapy in a metastatic setting will be enrolled and given pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations (2 years), with Objective Response Rate (ORR) using RECIST 1.1 as the primary study endpoint. The study applies a Simon two-stage design, where if at least 3 out of 22 evaluable patients achieve CR/PR in stage I, the study will proceed to stage II. Results: To date, 84 breast cancer patients were screened for germline A3Bdel, of whom 46 (54.8%) were heterozygous carriers and 12 (14.3%) were homozygous carriers. The study enrolled 22 female A3Bdel carriers with a median age of 59.4 years (range: 32.1, 82.9 years) between September 2020 and September 2021 for stage I analysis. On average, patients received 2 prior lines of chemotherapy in a metastatic setting [6 with 1, 8 with 2 and 8 with 3 lines of prior chemotherapy]. Complete response (CR) was observed in one patient, while partial response (PR) was observed in 4 patients, with an ORR of 22.7% (5 over 22 subjects) in stage I, meeting the pre-defined criteria to proceed to stage II. Notably, the patient with complete response had received 2 prior lines of chemotherapy, whereas of the patients with partial response, 1 had received 1 prior line and 3 had received 3 prior lines of chemotherapy in a metastatic setting. As the observed ORR was greater than the value of r1 (13.6%), the study has met the statistical criteria to proceed to the stage II enrolment with an additional 18 patients required to complete the entire study. Conclusions: Single agent pembrolizumab demonstrates promising efficacy in germline A3Bdel carriers, who constitute almost two-thirds of Asian patients. Clinical trial information: NCT03989089.
Association of interleukin-enhanced factor 2 (ILF2) expression with prognosis and clinico-genomic features in breast cancer (BC).
Authors: Bustos Matias A. , Yin Jun , Brodskiy Pavel , Kang Irene , Graff Stephanie L. , Sammons Sarah , Dawar Richa , Spetzler David , Hoon Dave S. B.
Published: June 2022

1030

Background: Novel prognostic and predictive biomarkers beyond traditional histological subtypes are needed to better inform outcomes and enhance therapy guidance in breast cancer (BC). We have previously reported that ILF2 was overexpressed in TNBC cell lines and has a functional role in DNA and RNA metabolism, making it a promising biomarker for risk assessment and treatment decisions. Herein, we aim to leverage a large clinico-genomic dataset to further characterize ILF2 in BC patients (pts). Methods: A total of 9456 BC tissue samples underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Analyses included next generation sequencing of DNA (592 Gene Panel, or Whole Exome Sequencing), and RNA (Whole Transcriptome Sequencing), and immunohistochemistry (IHC). Wilcoxon and Fisher’s exact were used to determine statistical significance. Overall survival (OS) was obtained from insurance claims and Kaplan-Meier estimates were calculated. Spearman correlation was used to identify highly correlated genes (ρ>0.6) with ILF2 and significant genes that were subsequently analyzed via pathway analysis using STRING. Results: BC pts were grouped into ILF2-High (H, top quartile) and ILF2-Low (L, bottom quartile) based on mRNA expression (TPM). ILF2-H pts were significantly younger (73 vs 80% for pts >50), enriched in ductal histology (90.9 vs 77.7%), TNBC subtype (48.9 vs 18.9%), and had a higher CNS metastases rate (4.3 vs 1.4%) compared to ILF2-L pts (all q<0.0001). ILF2 overexpression was associated with significantly inferior OS in all BC pts (HR 3.38, 95%CI: 2.97 – 3.84); when stratified into known BC hormonal receptor (HR) subtypes, ILF2 was prognostic in both HR+ BC (HR 1.7, 95 CI: 1.34-2.19) and TNBC (HR 3.8, 95 CI: 3.1-4.7), all p<0.0001. In TNBC (n=2468), ILF2-H was associated with a higher frequency of TP53 mutations(mt), lower rate of PIK3CA mt and higher amplification of CCNE1 and FGF23; in HR+/HER2- BC (n = 5071), an association with a higher rate of TP53 mt, PD-L1 expression, NOTCH2 and CCND2 amplification was seen (Table). No significant molecular correlation with ILF2 was seen in HR-/HER2+ BC (n=682). In TNBC, ILF2 expression was significantly correlated with genes involved in spliceosome, cell cycle and RNA transport pathways. In HR+/HER2- BC, ILF2-correlated genes were significantly enriched in mismatch repair and DNA replication pathways (p<0.05 for all factors individually). Conclusions: High expression of ILF2 is associated with a poorer prognosis independent of subtype in BC and our study warrants further investigation on ILF2 as a diagnostic and therapeutic target.[Table: see text]
Survival of elderly patients with HER2+/HR- metastatic breast cancer in clinical practice: SEER-Medicare data 2012-2016.
Authors: Ou Zhonghui , Spring Laura , Nohria Anju , Seeger John D. , Murimi-Worstell Irene
Published: June 2022

1039

Background: Older patients with human epidermal growth factor 2-positive (HER2+) metastatic breast cancer(mBC) are underrepresented in clinical trials. We aim to assess the overall survival (OS) and breast cancer-specific survival of elderly women with de novo HER2+/hormone receptor-negative (HR-) mBC in a real-world setting. Methods: Elderly women with HER2+/HR- mBC treated with chemotherapy and/or HER2-targeted agents and with continuous Medicare Part A, B, and D coverage 1-year before diagnosis were identified from the SEER-MEDICARE database 2012-2016. Patients were retrospectively followed from metastatic diagnosis until death, disenrollment from Medicare A, B, or D, or end of the observation period. Patients' year and month of diagnosis and death were retrieved from SEER. Death dates were verified with Medicare records reported by the Social Security Administration (SSA). For all-cause deaths, Kaplan-Meier analysis was used to estimate overall survival. The cumulative incidence competing risk (CICR) method based on cumulative incidence function (CIF) was used to estimate breast cancer-specific death incidence. Results: Seventy-three patients (mean age at diagnosis, 75.0±7.7 years) met the inclusion criteria. Among them, 56 were treated with trastuzumab ± pertuzumab /chemotherapy as first-line treatment, and 17 were treated with chemotherapy only. The median time to initiate trastuzumab-based treatment from diagnosis was 2.5 months, and the longest trastuzumab treatment length was over 44 months. The median follow-up for OS was 13 months. One patient developed stomach cancer 6 months after breast cancer diagnosis. In Kaplan-Meier analysis, censoring or not censoring this patient after second cancer development resulted in a median OS of 19 months (95% CI, 9-24 months) and 18 months (95% CI, 9-22 months). The OS at the end of 46 months was approximately 25%. Five patients died from other causes, including lung cancer, cerebrovascular diseases, aortic aneurysm and dissection, pneumonia and influenza, and heart diseases during treatment. Considering these competing risks, 50% (95% CI, 36%-64%) of patients specifically died from breast cancer between 21 and 22 months, estimated by the CICR method. Conclusions: Our study observed a shorter OS among HER2+/HR- mBC elderly patients in clinical practice than the OS of 40.8 and 56.5 months among younger patients in the CLEOPATRA trial, suggesting that age is an important prognostic factor for breast cancer survival. The presence of second cancer and other competing risks led to overestimating the probabilities of breast cancer-specific death and resulted in a shorter OS using the Kaplan-Meier method. The CICR method is more relevant to estimate the breast-cancer-specific death incidence.
Treatment patterns and their impact on the outcome of patients with HR+/HER2+ metastatic breast cancer in a large real-world cohort.
Authors: Carausu Marcela , Carton Matthieu , Dieras Veronique C , Petit Thierry , Guiu Lahaye Severine , Veyret Corinne , Goncalves Anthony , Augereau Paule , Ferrero Jean-Marc , Levy Christelle , Ung Mony , Desmoulins Isabelle , Debled Marc , Bachelot Thomas , Eymard Jean-Christophe , Pistilli Barbara , Frenel Jean-Sebastien , Chevrot Michaël , Mailliez Audrey , Cabel Luc
Published: June 2022

1043

Background: The place of endocrine therapy (ET) in the treatment of hormone receptor-positive (HR+), HER2+ metastatic breast cancer (MBC) is still not clearly defined. Data suggest that blocking both HR and HER2 signaling pathways could be an efficacious strategy to overcome secondary resistance. Methods: We aimed to retrospectively evaluate the impact of first line (L1) therapy for HR+/HER2+ MBC patients (pts) included between 2008- 2017 in the French real-world ESME MBC database (NCT03275311). Our primary endpoints were median overall survival (mOS) and median first progression-free survival (mPFS1). We used descriptive statistics and the Kaplan-Meier method to report patient characteristics and outcomes. Cox proportional hazards models and a propensity score were constructed to report and adjust for prognostic factors. Results: From the 23,501 female pts in the ESME MBC cohort, 1,790 pts had HR+/HER2+ MBC treated with Trastuzumab (T, n=1,089) or Trastuzumab-Pertuzumab (TP, n=701) during L1. Among them, 1,584 pts received antiHER2 therapy+CT+/-ET and 206 pts, antiHER2+ET only. Pts with antiHER2+CT+/-ET had more often ECOG performance status 0 (29.5% vs 15.8%, p<0.001), grade III tumors (36.6% vs 25.6%, p=0.007), time to MBC < 6 mo (51.6% vs 29.1%, p<0.001), TP as antiHER2 therapy (43.2% vs 9.4%, p<0.001), ≥3 metastatic sites (23.2% vs 14.8%, p=0.007), visceral metastasis (56.5% vs 42.4%, p<0.001), and less often bone-only disease (18.4% vs 35%, p<0.001) than pts with antiHER2+ET. In multivariable analysis, antiHER2+CT+/-ET was not superior to antiHER2+ET (Table), while TP was superior to Trastuzumab, and this result was confirmed by matching pts using a propensity score ( p=0.76 for mOS and p=0.85 for mPFS1). Using the time-dependent ET variable among pts with antiHER2+CT, pts with maintenance ET had significantly better PFS1 and OS than those without (adjusted HR for PFS1=0.70 [95%CI 0.60-0.82], adjusted HR for OS=0.47 [95%CI 0.39-0.57], p<0.001). Conclusions: These data suggest that endocrine therapy could be an interesting less toxic alternative to chemotherapy in combination with antiHER2 therapy as first line treatment for HR+/HER2+ MBC pts.[Table: see text]
Post-recurrence survival in asymptomatic compared with symptomatic metastatic breast cancer: A multicenter retrospective study.
Authors: Kuba Sayaka , Maeda Shigeto , Minami Shigeki , Moriuchi Hiroki , Tanaka Aya , Akashi Momoko , Morita Michi , Sakimura Chika , Baba Masayuki , Otsubo Ryota , Matsumoto Megumi , Yamanouchi Kosho , Yano Hiroshi , Kanetaka Kengo , Nagayasu Takeshi , Eguchi Susumu
Published: June 2022

1049

Background: Asymptomatic metastatic breast cancer (mBC) is often detected using tumor marker or imaging tests in Japan. At the ASCO 2019, we reported on mBC detection, the distribution of symptomatic and asymptomatic disease by subtype (abstract e12568). We aimed to determine whether there are differences in post-recurrence survival (PRS), and treatment between asymptomatic and symptomatic MBCs, and identify factors associated with PRS. Methods: We performed a multicenter, retrospective analysis of patients with mBC treated in our hospitals from 2008 to 2018. Patients were divided into asymptomatic and symptomatic MBCs to compare their prognosis by breast cancer (BC) subtypes: luminal (hormone receptor positive/human epidermal growth factor 2 [HER2] negative), HER2 (any hormone receptor/HER2 positive), and triple-negative (TN) (hormone receptor negative/HER2 negative). Results: Of 204 patients with mBC (114 asymptomatic, 90 symptomatic), PRS was longer in asymptomatic mBC than in symptomatic mBC (median survival: 55 months vs. 29 months; p < 0.001) and tended to have longer overall survival (OS) (110 months vs 72 months, respectively; p = 0.09). In multivariate analysis, TN, recurrence-free survival (RFS), multiple metastasis sites, and symptomatic disease were independently predictive of PRS (Table). In luminal and HER2, PRS trended higher in the asymptomatic group than in the symptomatic group (luminal: 54 months vs. 41 months; p = 0.08, HER2: 71 months vs. 27 months; p = 0.09), but without significant difference in OS (luminal: 112 months vs. 124 months; p = 0.91, HER2: 113 months vs. 72 months; p = 0.40). In the luminal group, 13 patients (11%) were treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. The median PRS was 80 months for luminal patients with three factors — longer than 4 years of RFS, a single metastasis site, and asymptomatic disease. The duration of endocrine therapy did not differ between groups; however, the patients with luminal BC in the asymptomatic group had longer chemotherapy than those in the symptomatic group. In TN, PRS was very short (asymptomatic, 28 months; symptomatic, 10.5 months; p = 0.01). Conclusions: We demonstrated that asymptomatic MBC and symptomatic MBC differed in terms of subtypes, prognosis, and duration of chemotherapy in the luminal group. Therefore, unique treatment strategy for asymptomatic or symptomatic MBC should be developed. [Table: see text]
The frequency of second primary malignancies and colonic polyps in Lynch syndrome with MSI tumors following immune checkpoint blockade.
Authors: Harrold Emily , Patel Zalak , Maio Anna , Cercek Andrea , Yaeger Rona , Segal Neil Howard , Reidy Diane Lauren , O'Reilly Eileen Mary , Desai Avni Mukund , Carlo Maria Isabel , Latham Alicia , Liu Ying L , Mandelker Diana , Markowitz Arnold , Offit Kenneth , Shia Jinru , Diaz Luis A. , Stadler Zsofia Kinga
Published: June 2022

10505

Background: Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair genes and is characterized by microsatellite instability (MSI) status of associated tumors. MSI sensitizes tumors to immune checkpoint inhibition (ICI). The incidence of second primary malignancies and colonic polyps in LS patients with MSI tumors following ICI has not been evaluated. Methods: The Memorial Sloan Kettering LS database was queried for all patients with cancer who received ≥1 cycle of ICI using an IRB approved protocol. LS was confirmed by presence of a germline pathogenic/likely pathogenic alteration in a DNA mismatch repair gene ( MLH1, MSH2, MSH6, PMS2, EPCAM). Tumor and matched normal DNA sequencing was performed via MSK-IMPACT, an IRB approved protocol (NCT01775072). MSI status was assessed using MSIsensor. Results: At our center, 131 patients with LS received ICI mostly (73.3%) in the context of metastatic cancer. While 108 patients received ICI for an MSI tumor, 23 LS patients received ICI for a MSS (Microsatellite Stable) tumor (4 hepatobiliary, 3 colorectal, 3 CNS, 2 endometrial, 2 gastroesophageal, 2 renal, 2 sarcoma, 5 other). Five patients (3.8%) developed ≥1 second primary malignancy while on or following ICI comprised of an MSI small bowel adenocarcinoma, MSI upper tract urothelial cancer, 2 MSS prostate cancers, MSS HCC and MSI sebaceous neoplasm; 1 patient developed both MSS prostate cancer and MSI urothelial cancer on ICI. All five patients’ primary malignancy was MSI. Only a minority of patients underwent surveillance colonoscopies post completion of ICI (31.3%, (41/131)). Of these 41, nine (22%, (9/41)) were identified to have polyps including 8 tubular adenomas and 1 tubulo-villous adenoma. Median time to development of a polyp was 22 months (95% CI 16.82-27.18) from last colonoscopy and 13 months (95% CI 4-25 months) from last ICI. Notably amongst the 23 LS patients whose tumors were MSS, 14 had progression on ICI. Conclusions: Herein, we demonstrate that in LS-patients in receipt of ICI for cancer treatment, the risk of a second primary cancer and polyps remain high following treatment with ICI. Biological mechanisms underlying immune escape warrant further investigation. Surveillance strategies should be continued for LS patients post ICI.
Aromatase inhibitors for breast cancer therapy: Analysis of real-world FAERS data.
Authors: Findakly Dawood , Shi Runhua , Burton Gary Von , Master Samip R.
Published: June 2022

1051

Background: Aromatase inhibitors (AIs) are extremely effective adjuvant treatment in postmenopausal women with hormone receptor-positive breast cancer (HRPBC). We utilized the Food and Drug Administration Adverse Event Reporting System (FAERS) database to evaluate the musculoskeletal (MSK), fractures, and ischemic heart disease (IHD) adverse events (AEs) caused by AIs. Methods: We conducted a retrospective FAERS public database review to assess the MSK, fracture, and IHD AEs for the three AIs (anastrozole, letrozole, and exemestane) from 2001 through 2021. Chi-square was used to compare categorical variables. Results: A total of 31,683 AEs reports were identified, out of which, 15,140 (47.8%) were MSK, 13,311 (42.0%) were fracture, and 3,232 (10.2%) were IHD. The differences in AEs distributions among the three drug classes were statistically significant for MSK and fracture AEs (P < 0.001) but not reached statistical significance for IHD AEs (P = 0.140). MSK AEs were mostly reported with anastrozole, followed by exemestane, and letrozole in 35.23%, 33.97%, and 32.06%, respectively (P < 0.001). Compared to older individuals, younger adults (≤65 years) had higher rates of MSK AEs—mostly with anastrozole (38.43%, P < 0.001), followed by exemestane (36.37%, P = 0.006) and letrozole (34.28%, P < 0.001). Fracture AEs were mostly reported, in descending order, with letrozole, exemestane, and anastrozole in 12.07%, 11.41%, and 9.34% respectively (P < 0.001). Older adults (> 65 years) had higher rates of fracture AEs with letrozole (16.77%, P < 0.001) and anastrozole (10.37%, P < 0.001), while unable to demonstrate statistical significance with exemestane (13.48%, P = 0.108). Among older adults (> 65 years), IHD AEs were significantly reported with anastrozole (21.56%, P < 0.001) and exemestane (14.18%, P = 0.016) but no statistical significance reached for letrozole (14.12%, P = 0.528). Conclusions: The findings in this study highlight trends for selected AEs with various AI regimens, provide further insights, and help guide therapeutic decisions for patients with HRPBC.