bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patterns of relapse after immunotherapy in patients with high-risk neuroblastoma.
Authors: Moerdler Scott , Naranjo Arlene , Tenney Sheena , Bagatell Rochelle , Yu Alice L. , London Wendy B. 
Published: June 2022

10043 Background: While the addition of anti-GD2 immunotherapy led to improvement in outcomes in patients on the Children’s Oncology Group (COG) ANBL0032 study, relapse remains a concern. Prior studies demonstrated the prognostic importance of time to first relapse, however, the effect of immunotherapy on timing and patterns of relapse in neuroblastoma (NBL) have yet to be evaluated. The purpose of this exploratory analysis was to describe the impact of immunotherapy on patterns of relapse in patients with high-risk NBL, including a descriptive comparison of sites of relapse based on post-consolidation treatment received [dinutuximab with cytokines and isotretinoin (DIN) vs isotretinoin alone (ISO)]. Methods: A retrospective, descriptive analysis of patients on ANBL0032 was performed, including patients randomized to DIN or ISO and those non-randomly assigned to DIN after ISO arm closure. Pt characteristics including age, stage, MYCN amplification status, tumor grade, mitosis-karyorrhexis index (MKI) and ploidy were summarized descriptively and relapse sites were tabulated. For DIN patients who subsequently relapsed, overall survival (OS) was calculated starting from the time of first relapse after enrollment on ANBL0032 (“post-relapse OS”). Kaplan-Meier OS curves were generated based on site of relapse. Results: The analytic cohort included 1,431 (DIN = 1,327; ISO = 104) patients. Among DIN patients, 492 relapsed, many in > 1 site. In the randomized cohort (n = 248), 122 relapsed (DIN = 68/144; ISO = 54/104). The frequencies (DIN; ISO) by site of relapse in the randomized cohort were: bone (53%; 54%), CNS (16%; 11%), lymph node (13%; 17%), abdominal (10%; 17%), paraspinal (6%; 2%), liver (3%; 4%), other soft tissue (22%; 7%). A higher proportion of ISO patients had marrow relapse (29.4% DIN; 48.2% ISO); however, the proportion of DIN patients with lung relapses appeared higher (9% vs 2%). Among all relapsed patients, the proportion with bone relapse did not appear to differ between treatment groups, regardless of MYCN status. Among patients with MYCN amplified disease, the proportion with marrow relapse did not appear to differ based on treatment [21/149 (14.1%) DIN; 3/20 (15.0%) ISO]; however, among patients with MYCN non-amplified disease, the proportion with marrow relapse appeared higher in the ISO group [16/23; 69.6%] vs the DIN group [52/193 (26.9%)]. Conclusions: In this exploratory analysis of patients on COG ANBL0032, the pattern for site of relapse appears to differ between patients treated with DIN vs ISO. While immunotherapy remains the treatment of choice in this population, the findings from this retrospective exploratory analysis warrant further investigation to decrease the risk for post-immunotherapy relapse. Clinical trial information: NCT00026312.
Informatics tools to implement late cardiovascular risk prediction modeling for population health management of high-risk childhood cancer survivors.
Authors: Noyd David H , Janitz Amanda , Baker Ashley , Beasley William , Etzold Nancy , Kendrick David , Oeffinger Kevin C. 
Published: June 2022

10048 Background: Marked improvements in outcomes for children with cancer and robust cohort studies with longitudinal follow-up inform evidence-based guidelines for survivors at risk for late cardiomyopathy. Clinical informatics tools to integrate data from multiple sources have the potential to catalyze population health management. Methods: The Oklahoma Childhood Cancer Survivor cohort was constructed from an institutional cancer registry of survivors diagnosed between 2005 and 2014 (n=382). Data elements (cumulative anthracycline, cumulative chest-directed radiotherapy, alkylator, and platinum exposures) were extracted from Passport for Care (PFC) to implement previously validated late cardiovascular risk prediction modeling from the Childhood Cancer Survivor Study (CCSS) for cardiomyopathy. Risk groups were compared to the Children’s Oncology Group (COG) Long-Term Follow-up Guidelines. Standard query language facilitated extraction of echocardiogram data from the electronic health record to determine adherence, defined as an echocardiogram within 27 months and 63 months from the last day of therapy for high and moderate risk survivors, respectively. Results: Sixty-nine percent (n=264) of survivors from the cancer registry were documented in PFC, of whom 29%, 56%, and 15% were classified as low, moderate, high risk, respectively, based on the CCSS late cardiomyopathy risk calculator. Concordance was modest for high and moderate risk groups (Kappa = 0.42 and 0.46, respectively) and good for the low risk group (Kappa = 0.77) compared to COG risk groups. There was excellent adherence to echocardiogram guidelines with 93% and 81% of moderate and high-risk survivors, respectively. There were significant differences based on risk group (p=0.02) and age at diagnosis (p<0.01). Conclusions: Clinical informatics tools represent a feasible approach to leverage discrete data elements regarding key treatment exposures from PFC to successfully implement previously validated late cardiovascular risk prediction models on a population health level. PFC promotes adherence to echocardiogram surveillance and serves as a platform for future interoperability to generate real-world data to improve survivorship-focused care. [Table: see text]
Improvements in life expectancy among childhood cancer survivors: Uneven gains and remaining challenges.
Authors: Yeh Jennifer M , Ward Zachary J. , Stratton Kayla , Armstrong Gregory T. , Chow Eric Jessen , Hudson Melissa M. , Morton Lindsay M. , Oeffinger Kevin C. , Diller Lisa , Leisenring Wendy M. 
Published: June 2022

10050 Background: Childhood cancer survivors are at risk for shortened lifespan. Projections of life expectancy (LE) by diagnosis can provide benchmarks for assessing improvements over time. Methods: We developed a simulation model to project risk for common, life-threatening chronic health conditions (CHCs; heart failure, myocardial infarction, valvular disease, stroke, secondary breast cancer, colorectal cancer, glial tumors, sarcomas) and excess mortality among 5-year survivors, based on patient characteristics (sex, age at diagnosis, diagnosis) and treatment exposures (chemotherapy, radiation dose). Risk was estimated using statistical models and Childhood Cancer Survivor Study data. Age-related CHC risks (SEER, NHLBI) and competing mortality (CDC Wonder) were based on national databases. We used model calibration to identify parameter sets that generated outcomes consistent with observed data. Model outcomes included conditional LE and 10-year survival probability at age 40. For comparisons to the general population, we simulated age-, sex-, and diagnosis year-matched individuals who faced only competing mortality rates. Results: Among a cohort representative of the CCSS (mean diagnosis age, 7.4 yrs), compared to the general population, the gap in LE among survivors diagnosed in the 1970s vs. 1990s decreased from 17 yrs (25%) to 11 yrs (17%). Changes in LE among survivors diagnosed in the 1990s vs. 1970s varied by diagnosis, with leukemia, lymphoma, and CNS tumor survivors estimated to live an additional 8 to 11 yrs (Table). In contrast, considerably smaller gains were estimated for sarcoma and renal tumor survivors (1–3 yrs) and a loss for neuroblastoma (-3 yrs). Among survivors who reached age 40, the probability of surviving an additional 10 years increased from 89% to 92% between 1970s vs. 1990s, with the greatest gains for lymphoma and CNS tumors. Conclusions: Although temporal changes in pediatric oncology are projected to result in LE gains among survivors, considerable variation is projected across diagnoses. These findings highlight the uneven success of improving treatments for all cancers. [Table: see text]
Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC): Biomarker (BM) analyses by next-generation sequencing (NGS) from the SOLAR-1 study.
Authors: Juric Dejan , Rugo Hope S. , Reising Albert , Ma Chong , Ciruelos Eva M. , Loibl Sibylle , Singer Christian F. , Sohn Joohyuk , Campone Mario , Conte Pierfranco , Iwata Hiroji , Ghaznawi Farhat , Miller Michelle Kristine , Taran Tetiana , Su Fei , Andre Fabrice 
Published: June 2022

1006 Background: PIK3CA mutations (mut; ~40% of HR+, HER2– ABC) are linked to poor prognosis. In SOLAR-1, ALP (PI3Kα-selective inhibitor and degrader) + FUL improved progression-free survival (PFS) vs placebo (PBO) + FUL in pts with PIK3CA-mutated HR+, HER2– ABC. Here, we focus on efficacy data by gene alterations in SOLAR-1 PIK3CA-altered (alt) cohort. Methods: SOLAR-1 was a phase 3, randomized, double-blind study of ALP (or PBO) + FUL in HR+, HER2– ABC progressing on/after an aromatase inhibitor. Baseline tissue samples with enough quantity/quality (N = 398) were retrospectively tested by NGS (FoundationOne CDx 324-gene panel) and pts grouped by PIK3CA-alteration status. Clinical benefit was assessed using PFS and hazard ratio (HR) based on tumor mutational burden (TMB) and gene alteration status in the PIK3CA-alt cohort. No multiplicity adjustment was made. Results: PIK3CA-alt (ALP, n = 120; PBO, n = 117) and PI3KCA-non-alt (ALP, n = 81; PBO, n = 80) cohorts had differential gene alteration landscapes. In the PIK3CA-alt cohort, ALP + FUL clinical benefit was seen across TMB quartiles (Q1: 0 -<2.52, Q2: 2.52 -<3.78, Q3: 3.78 -<5.04, Q4: ≥ 5.04 mut/megabase). ALP + FUL had greater benefit in pts with alt vs non-alt FGFR1/ 2 (Table). ALP + FUL benefit was independent of alterations in TP53, ESR1, CCND1, MAP3K1, and ARID1A and limited in MYC- and RAD21-alt cohorts . ALP + FUL benefit was seen in pts with alt genes in the MAPK (HR [95% CI] vs PBO: alt 0.43 [0.23 - 0.80]; non-alt 0.56 [0.40 - 0.79]) and PI3K (in addition to PIK3CA; alt 0.68 [0.38 - 1.23]; non-alt 0.48 [0.34 - 0.68]) pathways, and implicated in CDK4/6i resistance (alt 0.52 [0.30 - 0.89]; non-alt 0.53 [0.37 - 0.76]). Conclusions: The unique mut profile of PIK3CA-alt tumors did not affect ALP + FUL benefit in pts with HR+, HER2– ABC. Clinical benefit was maintained regardless of alterations in most BMs, including ESR1 and genes implicated in CDK4/6i resistance, consistent with ALP targeting the PIK3CA driver oncogene. Clinical trial information: NCT#02437318; EUDRA CT#2015-000340-42. [Table: see text]
Contributions of screening, early-stage treatment, and metastatic treatment to breast cancer mortality reduction by molecular subtype in U.S. women, 2000-2017.
Authors: Caswell-Jin Jennifer Lee , Sun Liyang , Munoz Diego , Lu Ying , Li Yisheng , Huang Hui , Hampton John M. , Song Juhee , Jayasekera Jinani , Schechter Clyde , Alagoz Oguzhan , Stout Natasha K. , Trentham-Dietz Amy , Mandelblatt Jeanne S. , Berry Donald A. , Lee Sandra J. , Huang Xuelin , Kurian Allison W. , Plevritis Sylvia 
Published: June 2022

1008 Background: Treatment for metastatic breast cancer has advanced since 2000, but we do not know if those advances have reduced mortality in the general population. Methods: Four Cancer Intervention and Surveillance Network (CISNET) models simulated US breast cancer mortality from 2000 to 2017 using national data on mammography use and performance, efficacy and dissemination of estrogen receptor (ER) and HER2-specific treatments of early-stage (stages I-III) and metastatic (stage IV or distant recurrence) disease, and competing mortality. Models compared overall and ER/HER2-specific breast cancer mortality rates from 2000 to 2017 relative to estimated rates with no screening or treatment, and attributed mortality reductions to screening, early-stage or metastatic treatment. Results of an exemplar model are shown. Results: The mortality reduction attributable to early-stage treatment increased from 35.8% in 2000 to 48.2% in 2017, while the proportion attributable to metastatic treatment decreased slightly from 23.9% to 20.6%. The increasing contribution of early-stage treatment reflects the transition of effective metastatic treatments to early-stage disease: accordingly, ten-year distant recurrence-free survival improved (82.5% in 2000, 87.3% in 2017; for ER+HER2+, 78.2% to 90.9%). Survival time after metastatic diagnosis also increased, doubling from 1.48 years in 2000 to 2.80 years in 2017, with the best survival for women with ER+HER2+ cancers (4.08 years) and worst for ER-HER2- (1.22 years). Conclusions: Advances in metastatic breast cancer treatment are reflected in lower population mortality, both through transition to early-stage treatment and gains for women with metastatic disease. These results may inform patient/physician discussions about breast cancer prognosis and expected benefits of treatment. [Table: see text]
Use of real-world data (RWD) to assess the utility of cell-free circulating tumor DNA (cfDNA) in identifying resistance to early treatment in advanced breast cancer (aBC).
Authors: Wander Seth Andrew , Weipert Caroline , Liao Jiemin , Zhang Nicole , Razavi Pedram 
Published: June 2022

1011 Background: The approvals of CDK4/6 inhibitors (CDK4/6i) and alpelisib (a PI3Ka inhibitor, PI3Ki) have overhauled early treatment of hormone positive aBC. While some clinical trials have investigated mechanisms of resistance to these drugs, their impact on tumor evolution requires further exploration. Here we use cfDNA to examine molecular changes pre- and post-CDK4/6i or PI3Ki treatment and use RWD to assess the impact of putative resistance alterations on response to treatment. Methods: Patients (pts) with aBC were identified via the Guardant INFORM database and included if they had a cfDNA test within 90 days prior to therapy initiation and/or 90 days after therapy discontinuation with CDK4/6i or PI3Ki. Pts with RB1 loss of function (LOF) alterations (alts) who received CDK4/6i and pts with PTEN LOF alts who received PI3Ki were separately identified, and these cohorts were matched 1:3 with a RB1/PTEN negative population respectively, by age (+/- 5 years), sex, year of cfDNA test, and line of therapy. Log-rank tests were used to assess differences in time to discontinuation (TTD) and time to next treatment (TTNT). Results: Differences in the frequencies of certain alts detected in pts pre- and post-CDK4/6i or PI3Ki treatment are shown (Table). Pts with RB1 LOF alts prior to the start of CDK4/6i had significantly worse TTD and numerically worse TTNT versus controls (TTD = 3 mos vs 4.7 mos, p=0.018; TTNT = 7.3 mos vs 8 mos, p=0.082). Pts with PTEN LOF alts prior to start of PI3Ki had no significant difference in TTD or TTNT versus controls (TTD = 4.1 mos vs 4.1 mos, p=0.92; TTNT = 7.4 mos vs 7 mos, p=0.32). Notably, 54% of pts receiving CDK4/6i and 84% of pts receiving PI3Ki were on their third or later line of therapy. Conclusions: Using cfDNA, we were able to further characterize the resistance landscape of both CDK4/6i and PI3Ki, and identified specific ESR1, RB1 and PTEN alterations that appear likely to occur under the pressure of therapy. Our real-world analysis examining RB1 LOF alts added further evidence to suggest it may be both a primary and acquired resistance mechanism to CDK4/6i. As a non-invasive alternative to tissue biopsies, this data further illustrates that cfDNA can provide unique insight into tumor evolution and disease progression in the aBC setting. [Table: see text]
Characterization of alpelisib-associated hyperglycemia in metastatic breast cancer.
Authors: Shen Sherry , Chen Yuan , Carpio Andrea , Chang Cassandra , Iyengar Neil M. 
Published: June 2022

1016 Background: For women with metastatic hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative breast cancer, the combination of alpelisib and fulvestrant improves progression-free survival in those with PIK3CA mutations. Hyperglycemia is a major toxicity of PI3K inhibitors including alpelisib, which limits the clinical efficacy of these drugs due to interrupted/reduced dosing and discontinuation. In the SOLAR-1 trial that led to the Food and Drug Administration (FDA) approval of alpelisib, over 60% of patients developed hyperglycemia of any grade, and over 36% developed grade 3-4 hyperglycemia. Here we describe the incidence and treatment of alpelisib-associated hyperglycemia in a single center cohort. Methods: Patients with metastatic breast cancer who received alpelisib on a clinical trial or as part of standard care from 2013-2021 at Memorial Sloan Kettering Cancer Center were included in this retrospective study. Patient and tumor characteristics and pre-treatment body mass index (BMI), hemoglobin A1c, and serum glucose levels were abstracted from medical records. Alpelisib dose interruptions, reductions, or discontinuation was recorded as well as endocrinology consultation and use of anti-hyperglycemic agents. Date of progression and/or death were recorded where applicable. Results: 247 patients were included in this study, among whom 245 (99.1%) were female and 198 (80.1%) were white. 100 (40.5%) were treated on a clinical trial. Median baseline BMI was 25.4 kg/m2. Among 164 patients with baseline hemoglobin A1c levels available, 93 (56.7%) patients had normal hemoglobin A1c, 54 (32.9%) had prediabetes, and 17 (10.4%) had diabetes. 152 patients (61.5%) developed hyperglycemia of any grade; 56 (22.7%) developed grade 3 and 16 (6.5%) developed grade 4 hyperglycemia. The median time to onset of hyperglycemia was 16 days. BMI ≥25 kg/m2 or hemoglobin A1c ≥5.7% were strongly predictive of development of any-grade hyperglycemia ( p= 0.036 and p< 0.001, respectively) and grade 3-4 hyperglycemia ( p< 0.001 for both). Among those who developed hyperglycemia, 101 (40.9%) received treatment; 69 patients (27.9%) required only 1 anti-hyperglycemic agent whereas 9 (3.6%) required ≥3 anti-hyperglycemic agents. 49 (19.8%) were referred for endocrinology consult. In 66 patients (26.7%), alpelisib was held until resolution of hyperglycemia; 42 patients (17%) required dose reductions, and 11 (4.5%) discontinued alpelisib due to hyperglycemia. There was no significant difference in progression-free survival by hyperglycemia status or severity of hyperglycemia. Conclusions: Overweight BMI and hemoglobin A1c in the prediabetes or diabetes range were strongly predictive of developing alpelisib-associated hyperglycemia. Management of these co-morbidities prior to alpelisib treatment should be strongly considered.
Largest evaluation of acquired resistance to sotorasib in KRAS p.G12C-mutated non–small cell lung cancer (NSCLC) and colorectal cancer (CRC): Plasma biomarker analysis of CodeBreaK100.
Authors: Li Bob T. , Velcheti Vamsidhar , Price Timothy Jay , Hong David S. , Fakih Marwan , Kim Dong-Wan , Falchook Gerald Steven , Delord Jean-Pierre , Dy Grace K. , Ramalingam Suresh S. , Strickler John H , Kurata Takayasu , Wolf Juergen , Sacher Adrian G. , Addeo Alfredo , Prenen Hans , Hindoyan Antreas , Anderson Abraham , Ang Agnes , Skoulidis Ferdinandos 
Published: June 2022

102 Background: Sotorasib, a specific, irreversible KRASG12C inhibitor, has been approved in multiple countries for adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received prior systemic therapy based on the global phase 1/2 CodeBreaK100 trial. Here we describe putative mechanisms of acquired resistance to sotorasib from the largest single dataset evaluated to-date. Methods: Patients with advanced KRAS p.G12C-mutated NSCLC or CRC from the CodeBreaK100 Ph1/2 trial who received sotorasib monotherapy at 960 mg once daily were analyzed for efficacy. Primary endpoint was objective response rate (ORR) assessed by central review. To investigate biomarkers of resistance to sotorasib, an exploratory endpoint was defined to examine acquired genomic alterations at disease progression. Plasma samples collected at baseline and progression were analyzed for genomic alterations with the 23-gene Resolution Bioscience ctDx Lung test for NSCLC and the 74-gene Guardant 360 ctDNA test for CRC. Acquired genomic alterations were defined by their absence at baseline and presence at progression. Results: In 174 pts with NSCLC and 91 pts with CRC-treated with sotorasib, the ORR were 41% and 12% respectively. Median progression-free survival and median overall survival were 6.3 months (mos) and 12.5 mos for NSCLC pts and 4.2 mos and 13.4 mos for CRC pts (median follow-up: 22.5 mos NSCLC; 12.5 mos CRC). A total of 67 NSCLC pts and 45 CRC pts had a plasma sample sequenced both at baseline and at progression. At least one new acquired genomic alteration at progression was detected in 19 (28%) NSCLC pts and in 33 (73%) CRC pts (Table). The acquired genomic alterations were heterogeneous in both NSCLC and CRC, with variants detected across multiple genes and pathways. The most prevalent putative pathway of resistance in both NSCLC and CRC was the receptor tyrosine kinase (RTK) pathway. Secondary RAS alterations occurred more frequently in CRC versus NSCLC pts (16% vs. 3%). Conclusions: Based on the largest descriptive dataset to-date, diverse mechanisms of acquired resistance occur in KRAS p.G12C-mutated NSCLC and CRC pts treated with sotorasib. New RTK pathway alterations frequently emerged at progression, highlighting the potential role for combining sotorasib with upstream inhibitors of RTK, such as SHP2 or EGFR inhibitors. Serial plasma DNA analysis revealed acquired resistance patterns that support the development of KRASG12C inhibitor combination therapies. Clinical trial information: NCT03600883. [Table: see text]
Chemotherapy shows better efficacy than endocrine therapy in patients with metastatic breast cancer with heterogeneous estrogen receptor expression.
Authors: Xie Yizhao , Du Xinyue , Tao Zhonghua , Zhao Yannan , Gong Chengcheng , Hu Xichun , Yang Zhongyi , Wang Biyun 
Published: June 2022

1050 Background: Heterogeneity of estrogen receptor (ER) expression has long been challenges for diagnosis and treatment strategy of metastatic breast cancer (MBC). A novel convenient way of ER detection using 18F-fluoroestradiol positron emission tomography/computed tomography (18F-FES PET/CT) offers a chance to screen and analyze MBC patients with ER uncertainty. Methods: MBC patients who received 18F-FES PET/CT were screened and patients with both FES positive (FES+) and negative (FES-) lesions were enrolled in this study. Progression‐free survival (PFS) was estimated by Kaplan-Meier method and compared by log-rank test. Results: A total of 635 patients were screened and 75 of 635 (11.8%) patients showed ER uncertainty. 51 patients received further treatment and were enrolled in this study. Among them, 20 (39.2%) patients received chemotherapy (CT), 21 (41.2%) patients received endocrine-based therapy (ET) and 10 (19.6%) patients received combined therapy (CT+ET). CT showed better progression-free survival (PFS) compared to ET (mPFS 7.1 vs 4.6 months, HR 0.44, 95% CI 0.20-0.93, P = 0.03). CT+ET did not improve PFS compared to either CT or ET alone (mPFS 4.4 months, P > 0.2). Conclusions: 18F-FES PET/CT could identify patients with ER heterogeneity. Patients with ER uncertainty showed better sensitivity to CT rather than ET. Combined therapy of CT+ET did not improve treatment outcome.