bluuebunny/crossref_metadata_2025 huggingface dataset:
Accelerated brain age and associated neurocognitive impairments in adult survivors of childhood cancer.
Authors: Phillips Nicholas Steve , Baedke Jessica L , Williams AnnaLynn , Ji Qing , Zhang Silu , Scoggins Matthew , Sabin Noah , Merchant Thomas E. , Gajjar Amar J. , Ness Kirsten K. , Hudson Melissa M. , Yasui Yutaka , Krull Kevin R.
Published: June 2023

10028

Background: Structural brain aging assessed from routine clinical MRI exams is associated with neurologic and neurocognitive impairments in older non-cancer populations yet is unexplored in childhood cancer survivors. Methods: Neurocognitive assessments and clinical 3-D T1 MRI whole brain images were obtained on 253 childhood cancer survivors (acute lymphoblastic leukemia = 118; brain tumor = 49; Hodgkin lymphoma = 86) and 43 community controls. Brain age was estimated using open-source Gaussian process regression software (BrainAgeR) on visually inspected, segmented, and normalized MRI scans. Benjamin-Hochberg adjusted T-tests were used to compare age-adjusted neurocognitive z-scores between controls and survivors. Linear regression tested associations between brain age acceleration (brain age-chronological age) and treatment (multivariable), and neurocognitive outcomes (univariable). Results: Survivors (mean(SD) age 31.2[8.9]) had poorer executive function (Trails B survivors -0.72 vs controls 0.32, p < 0.0001), processing speed (Grooved Peg Board -0.77 vs 0.05, p < 0.0001), memory (visual selection -0.73 vs -0.10, p = 0.0010; digit backward span -0.45 vs 0.08, p = 0.0304), vocabulary (WASI vocabulary -0.43 vs 0.14, p = 0.0007), and reading (WJ letter word -0.43 vs -0.05, p = 0.0006) compared to controls. In survivors, mean[95%CI] brain age was 7.5[6.4 to 8.6] years older than chronologic age; 0.65[-1.0 to 2.3] years for controls. Compared to males without cranial radiation, for females age≥10 years at cancer diagnosis treated with ≥40Gy cranial radiation, brain age acceleration was 13.35 years (p < 0.001), which worsened by an additional 9.81 years (p = 0.017) for those diagnosed < 10 years. Greater brain age acceleration was associated with a worse performance in executive function (β = -1.73, p < 0.001), processing speed (β = -2.18, p < 0.001), memory (β = -2.07, p < 0.001; β = -1.78, p < 0.029), vocabulary (β = -2.04, p < 0.001), and reading (β = -3.77,p < 0.001). Conclusions: Survivors of childhood cancer experience significant brain age acceleration that is associated with impairments in neurocognitive function. In non-cancer populations, accelerated brain age has been shown to predict late morbidities and mortalities. BrainAge is a promising surrogate biomarker that could predict cognitive decline and improve early detection of dementia risk. Finally, it highlights the risk of cranial radiation in < 10-year-old female cancer survivors.
Adherence to mercaptopurine (6-MP) and habit strength in pediatric acute lymphoblastic leukemia (ALL).
Authors: Yang Mira , Badawy Sherif Mohamed , Singh Revika , King Kathryn
Published: June 2023

10030

Background: Rates of adherence to mercaptopurine (6-MP) below 90% have been associated with increased relapse in pediatric patients with acute lymphoblastic leukemia (ALL). Habit strength has been associated with medication adherence through multiple mechanisms, including self-efficacy and social norms. The goal of this study was to investigate the relationship between habit strength, adherence to 6-MP, and health-related quality of life domains. Methods: This was a single center, cross-sectional study. A total of 52 participants, including 11 patients (ages 12-23, mean age 16 ± 4, 45% Female) and 41 parents/caregivers (ages 25-43, mean age 37 ± 5, 80% Female) of patients with ALL under the age of 18. Participants completed the Visual Analogue Scale (VASdose), PROMIS Medication Adherence Scale (PMAS), Self-Regulated Habit Index (SRHI), and PROMIS quality of life measures (PROMIS-CAT). Spearman’s rho correlations were used to assess relationships between variables. Eleven semi-structured interviews of patients and caregivers were conducted and analyzed using Grounded Theory coding and thematic analysis. Results: Overall, 81% (n = 42/52) of participants surveyed had high adherence to 6-MP (VASdose ≥95%); 91% (n = 10/11) of patients and 78% (n = 32/41 of parents/caregivers reported high adherence. The median VASdose and PMAS score were 100% (IQR 97-100) and 39.5 (IQR 38-40) across all participants, respectively. Participants with higher adherence, VASdose ≥ 95% and PMAS ≥ 39.5, reported less physiological stress (p = 0.02), and better cognitive function (p = 0.09) and peer relations (p = 0.08), compared to those with lower adherence. No significant correlation was found between medication adherence rate and habit strength. Emerging themes from qualitative coding included the influence of routine and automaticity on 6-MP as well as adherence strategies. Strategies such as reminders, care team communication, and developing personalized tools were cited by participants as potentially improving adherence in taking or administering 6-MP. Other facilitating participant characteristics included experience with medication administration, self-efficacy, and access to social support. Financial burden, scheduling conflicts, and medication access were common barriers cited by participants. Conclusions: Nearly one-fifth of our participants reported lower adherence to 6-MP (VASdose < 95%), which increases risk of relapse. Medication adherence to 6-MP was not associated with habit strength, but our results show preliminary associations between adherence rates and quality of life outcomes, such as physiological stress. Behavioral interventions are needed to better optimize adherence to 6-MP and improve health outcomes in pediatric ALL.
A phase 1b study of crizotinib in combination with temsirolimus in pediatric ALK- or MET-aberrated relapsed or refractory neuroblastoma (ITCC-053): Results of the phase 1 part.
Authors: Schellekens Kim , Schoot Reineke Anna , van Eijkelenburg Natasha K.A. , Huitema Alwin , Casanova Michela , Reinhardt Dirk , Marshall Lynley V. , Aerts Isabelle , Barone Giuseppe , Chesler Louis , Tall Jennifer , Hughes Debbie , Dandis Rana , Moreno Lucas , Winkler-Seinstra Pauline L.H. , Wilner Keith D. , Zwaan C Michel , van der Lugt Jasper
Published: June 2023

10036

Background: Preclinical data in neuroblastoma (NBL) models provided evidence that the addition of an mTOR inhibitor with crizotinib may overcome the relative resistance to ALK inhibitors (Berry et al., 2012, Cancer Cell). The primary objective of this phase 1b trial was to establish the recommended phase 2 dose (RP2D) of crizotinib in combination with the mTOR inhibitor temsirolimus in pediatric NBL patients. Methods: Patients aged 1-21 years with relapsed/refractory ALK/MET aberrated NBL were eligible to enroll onto stratum 2 of the CRISP trial (EudraCT: 2015-005437-53, ITCC-053), sponsored by Erasmus MC. This was an open-label, non-randomized, two-stage phase 1b dose finding study. Crizotinib was dose escalated using the EWOC method in four dose levels (DL) ranging from 100 mg/m2 to 280 mg/m2 twice daily (BID) in 28 day cycles. Temsirolimus was administered intravenously in a fixed dose of 60 mg/m2/week. Both starting doses were reduced compared to the single agent RP2D because of an expected CYP3A4 interaction. Primary endpoint was dose limiting toxicity (DLT) during cycle 1. Radiological disease assessments and blood sampling for pharmacokinetics were scheduled per protocol. Results: Nine NBL patients were enrolled onto stratum 2 between 06-2018 and 12-2022. Eight patients with a median age of 7 years (range: 1-12) received trial treatment. The temsirolimus dose was reduced to 40 mg/m2 after the first 3 patients based on unexpected toxicity. DLTs occurred in 2/3 patients treated with crizotinib at DL2 (200 mg/m2 BID); grade 3 elevated ALT (alanine aminotransferase) and grade 3 gastritis (temsirolimus dose; see table). No DLT occurred in 5 patients treated with crizotinib DL1 (150 mg/m2 BID). Dose re-escalation of crizotinib to DL2 was considered not feasible. The RP2D was established at 150 mg/m2 BID crizotinib with 40 mg/m2 temsirolimus. Frequent grade 3 treatment-related adverse events were anorexia, gastritis, oral mucositis (n = 2) and anemia (n = 3). Treatment, toxicity and response are summarized in table. Conclusions: We established a RP2D of 150 mg/m2 BID crizotinib in combination with 40 mg/m2 temsirolimus. The expansion cohort is currently open for enrollment. Clinical trial information: EUCTR2015-005437-53 . [Table: see text]
Healthcare resource use for pediatric low-grade glioma care: A cohort of linked electronic health records and claims data.
Authors: Cooney Tab , Yu Sandie , Daral Shailaja , Field Michelle , Krebs Blake , Kieran Mark , Manley Peter , Govinda Raju Sandya , Zelt Susan
Published: June 2023

10038

Background: Pediatric low-grade glioma (pLGG) is the most common brain tumor in children and is associated with persistent long-term tumor- and treatment-related morbidities. This study aims to characterize the costs associated with the treatment of pLGG. Methods: A retrospective study using the Optum de-identified Market Clarity Dataset linked claims (commercial, Medicare Advantage and Managed Medicaid beneficiaries) and electronic health records (EHRs) of cases ≤18 years of age, with an ICD-10 code for brain neoplasm and ≥1 physician notes between January 2017 and June 2018 was performed. Index date was the first claim or EHR with an ICD-10 code for brain neoplasm. Natural language processing was used to identify pLGG-relevant data from physician notes. The observation period included 3 months prior to index date and 6-month segments from index date for 36 months. Cases had either continuous insurance coverage or continuous EHR activity during this period. Results for procedures and medication use were reported as averages throughout the 36-month post-index follow-up period. Results: A total of 154 patients with pLGG were identified. Median age was 11 years (range 2–18). Among the cohort, 49% (n=76) were female; 75% (n=116) were non-Hispanic white, 13% (n=20) Hispanic, 5% (n=7) African American, 1% (n=1) Asian and 6% (n=10) other/unknown. Of benefits, 56% had commercial and 44% Medicaid. Brain imaging and neuropsychological evaluations were performed at least once in 85% and 57% of the cohort, respectively. Among pLGG relevant medications, 57% of the cohort used analgesics, 45% anti-emetics, 32% anxiolytics, and 29% anticonvulsants. A total of 100 patients received ≥1 pLGG disease control treatments: Of these, 53% underwent emergency brain surgery, 24% had planned brain surgery, 14% received chemotherapy, and 6% received targeted therapy. Of the 100 patients who received disease control treatments, 57% relapsed after first-line treatment; 37% of patients received 2 lines of therapy, and 20% of patients received ≥3 lines of therapy. Conclusions: Our findings show that patients with pLGG often require long-term medical care and high levels of healthcare resources to treat their disease and its sequalae. Additionally, a majority will relapse and face a higher burden of disease. Further studies using integrated data sources are warranted to help us understand the burden of pLGG and inform evidence-based health care planning for these patients.
Clinical application of ctDNA detection in Chinese pediatric patients with soft tissue sarcoma (STS).
Authors: Zhu Jia , Lu Suying , Wang Juan , Sun Feifei , Huang Junting , Que Yi , Zhen Zijun , Sun Xiaofei , Zhang Yizhuo
Published: June 2023

10041

Background: Circulating tumor DNA (ctDNA) is an effective and noninvasive supplementary approach for assessing minimum tumor burden in a range of solid tumors; however, studies on pediatric soft tissue sarcoma (STS) are limited. The purpose of the study was to assess the utility of ctDNA detection in predicting patient response and recurrence, and to inform treatment strategies through dynamic monitoring of ctDNA during the treatment of various types of pediatric STS. Methods: From January 2022 to January 2023, a total of 27 tissues and 112 plasma samples were obtained at baseline and during treatment. Utilizing the next-generation sequencing approach, ctDNA profiling was performed on tissue and plasma samples from 48 pediatric STS ( < 18 years old) with a panel of 481 sarcoma-specific genes (Nanjing Geneseeq Technology Inc.). Results: The study included thirty patients with rhabdomyosarcoma, nine Ewing sarcoma, and nine other subtypes of sarcoma, with 52.1% (n = 25) female. Seven patients were stages I-II, and 24 were stages III-IV. At baseline, ctDNA was identified in 56.25 % (18/32) of plasma before chemotherapy and 87.50 % (14/16) of plasma before surgery. Comparable mutational burdens were seen in baseline tissue and plasma samples, with an average of 3.8 and 3 mutations per sample, respectively. The concordance of detected mutations between tissue and plasma was 64.3%. The average plasma abundance (p = 0.007), maximum abundance (p = 0.0045), ctDNA concentration (hGE/ml) (p = 0.0005), and relative ctDNA abundance (p = 0.0083) of stage IV patients (n = 5) were higher than those of stage I-III patients (n = 6). Following surgical resection, four patients (25 %, 4/16) had detectable ctDNA. In the longitudinal monitoring, we found a high correlation (75.86 %, 22/29) between ctDNA trend and clinical response. Notably, ctDNA positive in Ewing sarcoma had the strongest correlation with clinical response. The inconsistency between ctDNA detection and clinical response could be attributed to the presence of bone lesions (57.1%, 4/7). One patient was observed to have positive ctDNA before any radiological findings. Conclusions: Our findings showed that it is feasible to use ctDNA to dynamically monitor tumor burden in pediatric soft tissue sarcoma, especially Ewing sarcoma. ctDNA may serve as a safe, non-invasive option complementary to imaging assessment of sarcoma, and further clinical benefits are being investigated.
Neurosurgical morbidity in pediatric supratentorial midline low-grade glioma: Results from the German LGG studies.
Authors: Simon Michèle , Weiß Sarah , Thomale Ulrich-Wilhelm , Schulz Matthias , Kandels Daniela , Schuhmann Martin , ElDamaty Ahmed , Krauss Juergen , Hernáiz Driever Pablo , Witt Olaf , Bison Brigitte , Pietsch Torsten , Astrid Gnekow
Published: June 2023

10044

Background: Surgical resection is a mainstay of treatment for pediatric low-grade glioma (LGG) within all current therapy algorithms, yet associated morbidity is scarcely reported. As supratentorial midline (SML) interventions are particularly challenging, we investigated the frequency of neurosurgical complications/new impairments aiming to identify their risk factors. Methods: Records were retrospectively analyzed from 318 patients with SML-LGG from successive German multicenter LGG studies, undergoing surgery between May 1998 and June 2020. Results: 537 operations (230 resections, 167 biopsies, 140 non-tumor procedures) were performed in 318 patients (54% male, median age: 7.6 years at diagnosis, 9.5 years at operation, 11% NF1, 42.5% optic pathway glioma). Surgical mortality rate was 0.93%. Applying the Drake classification, postoperative surgical morbidity was observed in 254/537 (47.3%) and medical morbidity in 97/537 (18.1%) patients with a 40.1% 30-day persistence rate for newly developed neurological deficits (65/162). Neuroendocrine impairment affected 53/318 patients (16.7%), visual deterioration 34/318 (10.7%). Postsurgical morbidity was associated with patient age <3 years at operation, tumor volume ≥80cm3, presence of hydrocephalus, complete resection, surgery in centers with less than median reported tumor-related procedures and during the earlier study period between 1998-2006, while the neurosurgical approach, tumor location, NF1 status or previous non-surgical treatment were not. Conclusions: Neurosurgery-associated morbidity was frequent in pediatric patients with SML-LGG undergoing surgery in the German LGG-studies. We identified patient- and institution-associated factors that may increase the risk for complications. We advocate that local multidisciplinary teams consider the planned extent of resection and surgical skills. [Table: see text]
18F-MFBG PET imaging in patients with neuroblastoma: Lesion targeting and comparison with MIBG.
Authors: Modak Shakeel , Mauguen Audrey , Basu Ellen M. , Price Anita , Behr Gerald , Min Ryan , Lyashchenko Serge K. , Schwartz Jazmin , Pandit-Taskar Neeta
Published: June 2023

10046

Background: 123I-MIBG gamma camera imaging (MIBG) is routinely used for the imaging of neuroblastoma. Limitations include need for two-day imaging schedule and lack of quantitative uptake measurements. Phase I study showed that 18 F-MFBG (MFBG), a positron-emitting analog of MIBG, is safe and feasible (PMID:28705916). In the follow-up phase II trial (NCT02348749) we evaluated MFBG PET imaging, comparing neuroblastoma lesion between the two modalities. Methods: Patients with known neuroblastoma underwent whole- body PET CT or PET-MR imaging one hour post-injection with 8mCi/1.7m2 of MFBG. All patients had concurrent MIBG scan with planar and SPECT-CT imaging without intervening therapy. MFBG and MIBG images were independently analyzed for lesion targeting; lesion number, site and uptake was noted for each patient and compared. Discordant lesions were further investigated with correlative imaging and/or clinical follow up. MFBG score was generated, similar to the modified Curie score for MIBG, for each patient. Results: 25 patients (median age 8 y) underwent MFBG scans at a median of 2 (range 0-24) days after MIBG scans; in one patient MFBG scan was performed 1 day before MIBG scan. No MFBG-related adverse events were noted. 24 patients had both MIBG and MFBG positive scans while 1 patient had both MIBG and MFBG negative scans. A total of 367 lesions were visualized on MFBG as against 217 on MIBG. There were no MIBG-positive that were negative on MFBG. A median number of 11 (range 0-57) lesions per patient were detected on MFBG scan. Uptake was noted in osteomedullary only, (n=13), soft tissue only (n=1) and both soft tissue and osseous lesions (n=10). MFBG detected a median of 6 (range 1-24) additional lesions in 19 patients. In 16/19 patients where follow up was available, the discordance was related to true positive disease, including at least 116 sites. Respective median curie scores were 3 (range:0-22) and 9 (range:0-24) with MIBG and MFBG respectively. Conclusions: MFBG scan detected disease in all patients with MIBG positive disease. MFBG detected similar or more lesions compared to MIBG in patients with neuroblastoma, with overall increased scores. Further analysis to evaluate impact on patient management is underway. Clinical trial information: NCT02348749 .
Predictors of cancer center-based follow-up among pediatric and adolescent/young adult cancer survivors.
Authors: Pang Emily , Smith Stephanie M. , Saynina Olga , Schapira Lidia , Chamberlain Lisa J.
Published: June 2023

10055

Background: Though guidelines recommend lifelong follow-up for pediatric and adolescent/young adult (AYA) cancer survivors, this has been challenging to implement in clinical practice. We constructed an institutional cohort of pediatric/AYA cancer survivors in order to evaluate follow-up patterns and identify predictors of cancer center-based follow-up. We hypothesized that follow-up would be lower for patients with greater individual- and area-level socioeconomic disadvantage and longer time since treatment. Methods: This retrospective cohort study used EHR data at an academic medical center. We included all patients who completed cancer treatment between 2010-2019 and were aged 0-29 years at last treatment date. Treatment was defined by diagnosis/procedure codes and medication records for chemotherapy, radiation, stem cell transplant, and cancer surgery. The primary outcome of cancer center-based follow-up was defined by clinic visits in an oncology department through 12/31/2022. Patients who died were excluded after the date of death. Multivariate logistic regression models (overall, age 0-19, age 20-29) evaluated the association of follow-up with age, sex, race/ethnicity, treatment intensity, insurance type, primary language, distance to cancer center, and area deprivation index (ADI, a composite measure of socioeconomic disadvantage). Results: 2210 patients were included with an overall rate of cancer center-based follow-up that decreased from 94% 1 year after treatment to 61% at 2-3 years, 45% at 4-5 years, and 35% at 6-7 years. Follow-up was not significantly associated with race/ethnicity, insurance type, primary language, or ADI for overall or age-specific cohorts. Patients >100 miles away had lower odds of follow-up. Increasing age was associated with decreased odds of follow-up, and this trend persisted over time since treatment (Table). Conclusions: Patterns of decreased pediatric/AYA cancer survivor follow-up were largely predicted by age and time since treatment. Further work is ongoing to understand drivers of follow-up disparities, including transfers of care and insurance type among AYA patients and the role of community support and telemedicine in healthcare access and health promotion. [Table: see text]
An age-specific pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) from DESTINY-Breast01, -02, and -03.
Authors: Krop Ian E. , Wildiers Hans , Hurvitz Sara A. , Cortes Javier , Im Seock-Ah , Iwata Hiroji , Andre Fabrice , Saura Cristina , Modi Shanu , Kim Sung-Bae , Egorov Anton , Mathias Elton , Cathcart Jillian , Cagnazzo Antonio , Cheng Yingkai , Park Yeon Hee
Published: June 2023

1006

Background: T-DXd is approved for use in pts with HER2+ unresectable or mBC after a prior anti-HER2-based regimen in the metastatic or (neo)adjuvant setting, based on the randomized phase 3 DESTINY-Breast03 study (Cortes et al. N Engl J Med 2022). Older pts with HER2+ mBC tend to have worse efficacy and safety outcomes, regardless of treatment (Evans et al. Cancer Res 2021). Outcomes of older pts treated with T-DXd have not been thoroughly examined. Here we report age-specific (<65 vs ≥65 years) efficacy and pooled safety analyses of T-DXd from DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03. Methods: DESTINY-Breast01 (data cutoff [DCO], March 26, 2021) and DESTINY-Breast02 (DCO, June 30, 2022) enrolled pts whose disease progressed on trastuzumab emtansine (T-DM1); DESTINY-Breast02 compared T-DXd to chemotherapy of physician’s choice. DESTINY-Breast03 (DCO, July 25, 2022) included pts previously treated with trastuzumab and taxane; pts received either T-DXd or T-DM1. Results: At baseline, there were 44 (23.9%), 85 (20.9%), and 49 (18.8%) pts ≥65 years of age who received T-DXd in DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03, respectively. At DCO, median pooled treatment duration with T-DXd was 13.1 mo (range, 0.7-44.0) for pts <65 and 12.4 mo (range, 0.7-45.1) for pts ≥65. Key efficacy data are shown in the Table. Any-grade treatment-emergent adverse events (TEAEs), grade ≥3 TEAEs, and serious AEs were observed in 99.6%, 53.6%, and 24.3% of pts <65 and 100%, 65.5%, and 32.2% of pts ≥65, respectively. There were 125 (18.7%) and 45 (25.4%) TEAEs associated with T-DXd discontinuation in pts aged <65 and ≥65, respectively. Any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 11.8% of pts <65 and 17.5% of pts ≥65; grade 5 events occurred in 0.9% and 0.6% of pts <65 and ≥65, respectively. Additional efficacy and safety data will be presented. Conclusions: Results from this pooled analysis further demonstrate that T-DXd has a favorable benefit-risk profile in pts ≥65 years, with slightly increased toxicity, as expected. Clinical trial information: NCT03248492 , NCT03523585 , NCT03529110 . [Table: see text]
Self-reported sleep difficulties and association with cognitive function in pediatric cancer survivors.
Authors: Stavinoha Pete , Waterman Grace , Carroll Bridgette , Holland Alice Ann , Gragert Marsha N , Yang Grace , Bai Jinbing , Swartz Maria Chang
Published: June 2023

10065

Background: Preventing and ameliorating cognitive impairment following treatment for pediatric cancer remains a persistent challenge, with recent literature examining lifestyle factors as possible targets for intervention. An association between sleep and cognitive impairment has been identified in adult cancer patients and survivors, yet information is limited for pediatrics. Thus, the primary goal of our retrospective study was to explore self-reported sleep difficulties in pediatric patients and survivors with mixed cancers. A secondary aim was to explore the impact sleep problems on specific cognitive functions. Methods: Children and adolescents who completed neuropsychological assessments at two large pediatric cancer centers (N = 298) were identified via medical record review. In addition to demographic data, clinically collected cognitive tests included Wechsler Working Memory (WMI), Processing Speed (PSI), and General Ability (GAI) indices. Objective attention measures included Conners Continuous Performance Test (versions II and 3) Omissions (O), Commissions (C), and Reaction Time (RT). Sleep Disturbance (SD) and Sleep-Related Impairment (SRI) were captured using pediatric self-report PROMIS scales. PROMIS cut points were used to categorize sleep issues within the study population and PROMIS scores were compared to reference population means. Multiple linear regression was used to identify relationships between cognitive domains and sleep factors. Common cancer-related clinical and demographic characteristics were controlled as covariates. Results: 21.5% of patients reported severe SD, while 12.8%, 15.9% and 49.7% reported moderate, mild, and within normal limits (WNL) SD, respectively. For SRI, 13.3% reported severe SRI, while 20.0%, 15.9% and 50.8% reported moderate, mild and WNL SRI, respectively. Mean SD and SRI were higher than in the reference populations (p = 0.000 for both measures). Pearson correlation results suggested a moderate relationship between SD and SRI (r = 0.489, p = 0.000). After controlling for covariates, multiple linear regressions indicated significant relationships between SD and GAI (p = 0.006), SD and O (p = 0.018), and SRI and WM (p = 0.006). Conclusions: Results suggested that ~50% of our pediatric cancer patients and survivors reported SD and SRI. SD was correlated with SRI in our sample, and regression analysis indicates a significant relationship between sleep problems and O, WM, and GAI in our sample. Findings from this retrospective study suggest a relationship between sleep problems and cognitive performance in pediatric cancer survivors. As a potentially modifiable factor to improve cognitive function in pediatric cancer survivors, sleep difficulties warrant more research to potentially guide interventions to better manage and improve cognitive function in this population.
Characterization of the immune microenvironment in matched primary and metastatic breast cancer lesions from the AURORA study: BIG 14-01.
Authors: Hilbers Florentine , Venet David , Agostinetto Elisa , Benelli Matteo , Guerrero Angel , Martins-Branco Diogo , Raimbault Alice , Fimereli Danai , Ferrando Lorenzo , Sommariva Sara , Biagioni Chiara , Paoli Marta , Llinas-Bertran Arnau , Dadiani Maya , Zoppoli Gabriele , Balic Marija , Albanell Joan , Vosberg Sebastian , Irrthum Alexandre , Salgado Roberto
Published: June 2023

1009

Background: Immunotherapy benefit in patients with metastatic breast cancer (MBC) is limited to patients with triple negative breast cancer and PD-L1 expression in the tumor sample. Multi-omics characterization of the anti-cancer immune response in MBC could provide novel insights into the mechanisms behind immune response failure. Methods: The AURORA program (NCT02102165) enrolled patients with MBC who received at most one line of treatment in the metastatic setting. RNA sequencing was performed on primary and metastatic lesions. Stromal tumor infiltrating lymphocytes (sTIL) were scored in line with the International Immuno-Oncology Biomarker Working Group for Breast Cancer recommendations. T cell and B cell receptor (TCR and BCR) analysis was performed with MiXCR. Deconvolution of bulk RNA sequencing data was performed using xCell. ImmuneScore-normalized Relative Abundance metastasis/primary Ratios (RAR) of immune cell types were calculated. All comparisons between primary and metastatic lesions were performed on matched samples. Wilcoxon signed-rank tests were used. Results: As expected, sTILs decreased from primary to metastatic lesion. However, 9% of metastatic lesions still had ⪰20% sTILs. Matched RNA expression data was available for 204 patients. Relative abundance of macrophages (RAR 3.3, p<0.001) and Th1 cells (RAR 1.5, p<0.001) was increased in the metastases, while Treg cells (RAR 0.12, p<0.001), CD8+ T cells (RAR 0.32, p<0.001) and B cells (RAR 0.32, p<0.001) decreased the strongest. Metastases with ⪰20% sTILs had higher Treg cells (p<0.001) and B cells (p<0.001) compared to metastases with low sTILs, which had more Th1 cells (p<0.001), mast cells (p<0.001) and NKT cells (p<0.001). De novo metastatic and synchronous primary samples had more BCR (p<0.001) and TCR (p<0.001) clones in common as compared to non-de novo metastatic cancers. Conclusions: sTIL percentage decreased from primary tumor to metastatic lesion. Metastatic lesions with many sTILs (⪰20%) were enriched for immune response suppressing regulatory T cells. [Table: see text]
BRACELET-1 (PrE0113): Inducing an inflammatory phenotype in metastatic HR+/HER2- breast cancer with the oncolytic reovirus pelareorep in combination with paclitaxel and avelumab.
Authors: Clark Amy Sanders , Zhao Fengmin , Klein Paula , Montero Alberto J. , Falkson Carla Isadora , Krill-Jackson Elisa , Rowland Kendrith M. , Sardesai Sagar D. , Incorvati Jason Anthony , Dillon Patrick Michael , Wolff Antonio C. , Loghmani Houra , Trauger Richard , Heineman Thomas Charles , Coffey Matthew C. , Miller Kathy
Published: June 2023

1012

Background: In preclinical studies, the oncolytic reovirus pelareorep promoted an inflammatory tumor microenvironment (TME) by promoting greater infiltration of tumor infiltrating lymphocytes and upregulating PD-1/PD-L1 expression, potentially increasing the efficacy of immune checkpoint blockade. The addition of pelareorep to paclitaxel (PTX) was associated with improved survival (10.4 vs. 17.4 mos., HR = 0.65, p = 0.1) in a prior trial, with the greatest benefit in patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) disease (N = 57; 10.8 vs. 21.0 mos., HR 0.60, p = 0.1). Methods: This is a randomized phase 2 study in pts with HR+/HER2- metastatic breast cancer. Patients must have progressed on at least one hormone therapy with a CDK4/6 inhibitor. After a safety run-in for Cohort 3, patients were randomized 1:1:1 to PTX-alone (Cohort 1), PTX + pelareorep (Cohort 2), or PTX + pelareorep + avelumab (Cohort 3). The primary endpoint was overall response rate (ORR) at week 16 according to RECIST v1.1 without formal comparison across groups. Toxicity, progression-free survival (PFS) and overall survival were secondary endpoints. Blood samples were collected at cycle 1-day 1 (C1D1), C2D1 and C4D1, and T-cell receptor sequencing was performed. Results: Forty-eight pts were enrolled between June 2020 and June 2022. Median age was 55.5 yrs, range 37-74. Forty pts (83%) had visceral disease. Six pts (12%) previously received everolimus, and 3 alpelisib. Thirteen pts (27%) received prior taxanes in the neo/adjuvant setting. Three pts who withdrew consent prior to starting therapy and 2 pts who discontinued treatment after week 1 were considered non-responders and were censored for PFS. The most common pelareorep-associated toxicities were fever, chills, and flu-like infusion reactions, which were occasionally severe enough to require hospitalization in 5 (15%) pts despite acetaminophen prophylaxis. Nine pts (33%) discontinued pelareorep and 6 (35%) discontinued avelumab due to toxicity. Pelareorep increased T-cell repertoire turnover, with identification and expansion of new and pre-existing T-cell clones by C2D1. Conclusions: The addition of pelareorep to PTX is an active regimen with a high 6-month PFS rate worthy of further study. One third of patients discontinued either pelareorep or avelumab due to toxicity, highlighting the need for attentive supportive care. Survival data is maturing. Clinical trial information: NCT04215146 . [Table: see text]
Efficacy of tucatinib+trastuzumab+capecitabine (TTC) after trastuzumab-deruxtecan (T-DXd) exposure in Her2-positive metastatic breast cancer: A French multicentre retrospective study.
Authors: Frenel Jean-Sebastien , Zeghondy Jean , Guerin Catherine , Mailliez Audrey , Volant Elsa , Poumeaud Francois , Patsouris Anne , Arnedos Monica , Bailleux Caroline , Cabal Julie , Galland Loick , De nonneville Alexandre , Guiu Lahaye Severine , Dalenc Florence , Pistilli Barbara , Bachelot Thomas , Martin Pierre , Bocquet Francois , Larrouquere Louis , Loirat Delphine
Published: June 2023

1014

Background: Recent guidelines have positioned T-DXd as a preferred treatment in the second line setting for HER2+ metastatic breast cancer (MBC). TTC is the preferred treatment in third line, however little is known on the efficacy of this combination after T-DXd exposure. Methods: We conducted a retrospective study in 12 French comprehensive cancer centers. All patients with HER2+ MBC treated with TTC after prior exposure to T-DXd were included. The primary end point was progression-free survival (PFS) in the whole population. Secondary end-points included overall survival (OS), PFS in subgroups and objective response rate. Results: Between 08/2020 and 12/2022, 101 patients were included. Median age was 56.4 y.o. (range 30.8 - 84.8). Median number of prior line of treatment for metastatic disease at TTC start was 4 (2 - 15). 82% and 95% of patients had received previous pertuzumab and T-DM1 respectively. The median duration of previous exposure to T-DXd was 8.9 months (1.4 - 31.4) and 82/101 (81%) patients had progressed under T-DXd while 19 had stopped T-DXd for toxicity or other reasons. TTC regimen was given as a 3rd line or 4th line for metastatic disease in 37/101 (37%) and beyond for the remaining patients. TTC was the immediate subsequent therapy to T-DXd for 86/101 pts (85%). With a median follow-up of 8.5 m (95%CI [7.7; 9.4]), 68/101pts (67%) have stopped TTC for progressive disease. Median PFS was 4.7 m (95%CI [3.8; 5.6]) and median OS not reached (95%CI [10.6; NA]) in the whole population. Patients treated with TTC as the immediate subsequent therapy to T-DXd, had a median PFS of 5.0 m (95%CI [4.0; 6.0]) and a median OS not reached (95%CI [11.9; NA]). Best response to TTC, evaluated by investigators in the 87/101 RECIST evaluable patients, was progressive disease, stable disease, partial response and complete response in 34%, 34%, 30% and 2% of patients respectively. At TTC initiation, 39 (39%) of patients had known brain metastases. Out of the 62 patients without known brain metastases at the initiation of TTC, 2 had brain metastases documented as a site of progression during TTC. Conclusions: In this large retrospective cohort, TTC shows significant efficacy for patients with HER2+ MBC previously exposed to T-DXd. Data and subgroup analyses will be updated for the meeting.
Trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low, hormone receptor-positive (HR+) unresectable and/or metastatic breast cancer (mBC): Exploratory biomarker analysis of DESTINY-Breast04.
Authors: Modi Shanu , Niikura Naoki , Yamashita Toshinari , Jacot William , Sohn Joohyuk , Tokunaga Eriko , Vidal Maria Jesus , Park Yeon Hee , Lee Keun Seok , Chae Yeesoo , Ueno Naoto T. , Prat Aleix , Suto Fumitaka , Kuwahara Yusuke , McEwen Robert , Feng Wenqin , Goto Hiroki , Orbegoso Cecilia , Cameron David A. , Tsurutani Junji
Published: June 2023

1020

Background: DESTINY-Breast04 (NCT03734029) showed improved progression-free survival (PFS) and overall survival for T-DXd vs TPC in pts with HER2-low (IHC 1+ or 2+/ISH-negative) mBC. We present exploratory biomarker analysis in pts with HER2-low, HR+ mBC. Methods: Biopsy specimens collected from 326 pts after prior treatment were analyzed using RNA-sequencing and intrinsic subtypes estimated by PAM50 gene expression. ESR1 and PIK3CA mutations and known gene alterations associated with resistance to CDK4/6 inhibitors (CDK4/6i) were assessed in baseline (BL) circulating tumor DNA (ctDNA) samples from 414 pts by Guardant OMNI. Association with objective response rate (ORR) and PFS was evaluated. Results: Frequencies of BL intrinsic subtypes in the T-DXd and TPC arms were 41.3% and 46.6% for Luminal A, 48.0% and 37.9% for Luminal B, and 9.0% and 11.7% for HER2 enriched, respectively. According to ctDNA results in the T-DXd and TPC arms, respectively, ESR1 mutations were observed in 51.3% and 54.0% of pts, PIK3CA mutations in 36.1% and 41.6% of pts, and at least one CDK4/6i resistance marker (pts with prior CDK4/6i) was detected in 71.5% and 70.2% of pts. Improved T-DXd efficacy was seen regardless of intrinsic subtype (Luminal A, Luminal B, HER2-enriched), ESR1 mutation, PIK3CA mutation, or CDK4/6i resistance markers (Table). Conclusions: Greater clinical benefit was consistently observed with T-DXd vs TPC independent of intrinsic subtype, ESR1 mutation, PIK3CA mutation, or known CDK4/6i resistance marker status. Clinical trial information: NCT03734029 . [Table: see text]
Clinical features, genomic landscapes, and survival outcomes of HER2-low breast cancer.
Authors: Juan Jin , Li Bin , Wang Biyun , Tao Zhonghua , Hu Xichun
Published: June 2023

1027

Background: Novel human epidermal growth factor receptor 2 (HER2)-directed antibody‒drug conjugates prompt the identification of the HER2-low subtype. To investigate whether HER2-low breast cancer can be defined as a distinct biological subtype, our study conducted a comprehensive analysis on the clinical and molecular features among patients with different HER2 statuses. Methods: Clinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database. Genomic data of breast tumor samples was generated by targeted NGS using a cancer-related gene panel. The cohort included 220 HER2-zero, 194 HER2-low and 165 HER2-positive patients according to the HER2 status from the most recent pathological results. Results: First, the clinicopathological characteristics of HER2-low patients were associated with hormone receptor (HR) status. Less lymph node invasion and higher bone metastasis in HER2-low patients were probably because of the higher percentage of HR-positive tumors in HER2-low patients than HER2-zero and HER2-positive patients (63.19%, 42.02% and 28.00%, respectively, p<0.0001). Second, HER2 status shifting from primary to recurrent breast cancer was common, with 38.1% and 48.4% of HER2-zero primary tumors converting to HER2-low tumors when they metastasized in the whole population and the HR-positive subgroup, respectively. Third, HER2-low patients had more brain and lung metastases and cases of de novo stage IV breast cancer than HER2-zero patients in the HR-positive subgroup. Fourth, germline BRCA2 mutations were observed only in HER2-low patients (11/139, 7.91%) and HER2-low tumors had more somatic PIK3CA mutations than HER2-zero tumors in the HR-negative subgroup. Fifth, HER2-low patients had a longer median overall survival (mOS) and median disease-free survival (mDFS) than HER2-zero patients (mOS:49.1 vs. 30.3 months, log rank P = 0.0005; mDFS: 28.17 vs. 20.27 months, log rank P =0.036), but difference was not evident when paired by HR status. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, and Cluster 2, which enriched in TP53 mutations, was significantly associated with worse outcomes, which provided novel insights into heterogeneity in HER2-low breast cancer. Conclusions: The clinical and molecular significance of HER2-low status was influenced by HR expression, and HER2-low tumors had distinct features in subtype analyses based on HR status. Our elaboration of molecular subtypes in HER2-low tumors encourages clinicians to consider the heterogeneity in HER2-low breast cancer.
Concordance between liquid and tissue biopsy in participants with newly diagnosed recurrent breast cancer.
Authors: Lohmann Ana Elisa , Ennis Marguerite , Goodwin Pamela Jean , Veitch Zachary William Neil , Brezden Christine , Jerzak Katarzyna Joanna , Baer Kathie , Martel Samuel , Lemieux Julie , Guimaraes Jose Luiz Miranda , Cescon David W. , Thirlwell Michael P. , Slade Megan , Di Caro Giuseppe , Wenstrup Rick , Ethier Josee-Lyne , Soldera Sara V.
Published: June 2023

1028

Background: Tissue biopsy is recommended to confirm breast cancer (BC) recurrence. Liquid biopsy [including circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA)] is a non-invasive approach for detecting cancer that may provide information to identify treatment choices and replace invasive biopsies. This ongoing study aims to assess the concordance between tissue and liquid biopsy testing in subjects presenting with suspicion of distant recurrence from BC. Methods: Patients with suspected metastatic BC were enrolled; tumour characteristics and treatment were recorded. Blood samples were collected within 30 days before tissue biopsy, or within 7-28 days after tissue biopsy and before any systemic or radiation treatment. Samples were shipped to EPIC Sciences and processed within 96 hours; after plasma isolation, nucleated cells were plated; slides and plasma were banked. CTCs were identified using Epic Sciences digital imaging and machine learning algorithms. Single-cell isolation for genomic ctDNA analysis was performed. Cell free DNA was analyzed using a validated NGS panel to detect ctDNA alterations. The presence of metastases was classified as suspicious, highly suspicious, definitely metastatic BC or other by the treating oncologist based on the patient's clinical presentation and biopsy pathology results. Epic Sciences classified samples into similar categories based on CTC and ctDNA assay results. These classifications were performed independently. Sensitivity of the Epic Sciences methodology to detect metastatic BC (as determined by the treating oncologist), and its false positive rate were calculated. Results: 100 patients were enrolled from June 2020 to October 2022; shipping delays precluded EPIC assays in six patients; 94 patients were analyzed. Of 83 cases deemed suspicious, highly suspicious, or definitely metastatic BC by the treating oncologist, 61 were also deemed so by Epic Sciences (sensitivity of 73.5%, 95% confidence interval, CI 63.1% - 81.9%). Of 66 cases assigned as suspicious, highly suspicious, or definitely metastatic BC by the Epic Sciences, 4 had new primary cancers (3 lung cancer, 1 hepatocarcinoma), for a false positive rate of 6.1% (95% CI 1.9% - 15.0%). One additional case was classified as un-specified adenocarcinoma (possibly breast) by the treating oncologist; resolution awaits further follow-up. Conclusions: Preliminary results show that 73.5% of distant BC recurrences were correctly identified by liquid biopsy. A small number of false positive results occurred in patients with other new primary cancers. Additional analyses with CTC characterization are ongoing. [Table: see text]
Metastatic patterns and outcomes by HER2 and hormone receptor (HR) status in patients (pts) with metastatic breast cancer (mBC).
Authors: Yuan Qianyu , Castellanos Emily , Fidyk Erin , Schwed Karen , Estevez Melissa , Nemeth Sheila , Linzmayer Robin , Cohen Aaron B.
Published: June 2023

1031

Background: HER2-low status in mBC is predictive of benefit to trastuzumab deruxutan, but whether it is biologically distinct from HER2-neg disease is unclear. To better understand the prognostic significance of HER2-low status, we assessed patterns of metastases and real world overall survival (rwOS) by HER2 and HR status. Methods: Pts with mBC diagnosis from 1/1/2011 to 5/31/2022 were selected from the nationwide deidentified Flatiron Health electronic health record (EHR)-derived database. HER2 and HR status was derived from human abstraction (IHC 0-1+/2+/3+, FISH pos/neg, ER/PR) and machine learning-extraction (to classify IHC 0/1+). HER2 and HR tests prior and up to 60 days after metastatic diagnosis date (met Dx date) were included, results closest to met Dx date were used. Sites of metastasis (SOM) were grouped into mutually exclusive groups: brain, non-visceral (bone, skin, lymph node) and visceral (liver, lung, etc). Metastatic patterns stratified by HR/HER2 status were compared using chi-square tests. The association between HER2 status and rwOS, stratified by HR status, was evaluated using Cox models adjusted for age, race/ethnicity, practice, SOM, SES, and stage. rwOS stratified by HR/HER2 status and SOM were estimated via KM analysis. Results: Among 22,932 pts with mBC, HER2-low prevalence was 49%. HER2-low mBC was more likely to be HR+ than HER2-neg or HER2+ (84%, vs 70% and 65%; p<0.01). Pts with HER2-low and HER2-neg mBC had similar SOM overall, distinct from HER2+. For example, among HR+ pts, HER2-low and HER2-neg pts were less likely than HER2+ pts to have brain (4% and 4% vs 10%; p<0.01) or visceral metastases (51%, 50% vs 58%; p<0.01) but more likely to have non-visceral metastases (45% and 46% vs 32%; p<0.01). Compared to HER2-low pts, HER2-neg pts had similar rwOS if HR+ (hazard ratio 1.02, 95% CI 0.98-1.08) and slightly worse if HR-neg (hazard ratio 1.18, 95% CI 1.03-1.21). rwOS varied by HR/HER2 status and SOM. Conclusions: Our findings indicate that HER2-low mBC has biologic similarities to HER2-neg mBC. While slight differences were observed between HER2-neg and HER2-low pts in the HR-neg subgroup, overall rwOS differences were associated more strongly with HER2+ status, HR+ status, and metastatic pattern, indicating that HER2-low status may be more informative as a predictive rather than a prognostic biomarker. [Table: see text]