bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence and prognosis of BRCAm, homologous recombination repair mutation (HRRm) or HR deficiency positive (HRD+) across tumor types.
Authors: Shao Changxia , Ren Yixin , Zhou Heng , Chen Cai , Dettman Elisha , Cristescu Razvan , Gozman Alexander , Jin Fan , Zhou Wei 
Published: June 2022

e18802 Background: BRCAm, HRRm, or HRD+ may be predictive of response to poly (ADP-ribose) polymerase inhibitors (PARPi) with/without immunotherapy (IO). However, there is limited data on the prevalence of these biomarkers and their impact on overall survival (OS) among patients who are not treated with PARPi or IO. Methods: This is a retrospective observational study across 15 available tumor types, using data from the de-identified Flatiron Health - Foundation Medicine (FMI) clinicogenomic database collected up to Dec 31, 2020. The de-identified data originated from ̃280 US cancer clinics (̃800 sites of care). Eligible patients were aged ≥ 18 years, diagnosed with advanced/metastatic solid tumors in 2018-2019. BRCAm, HRRm, and HRD were assessed by FMI F1CDx. HRD+ was defined as genomic loss of heterozygosity (gLOH) ≥16. OS analysis from second line therapy initiation (2L, primary index date) was performed as primary analysis since this population had high unmet medical need, and most patients were sequenced after 1L. Patients were excluded if PARPi/IO started on the index date or earlier or if patients died before the index date; and patients were censored as of PARPi/IO initiation if PARPi/IO was started later than the index date. OS was analyzed using the Kaplan-Meier method and Cox proportional hazards model, adjusted for age, sex, and tumor type. Results: A total of 9,462 patients with advanced/metastatic solid tumors were included, with 52% women and mean age of 66 years. The top five tumor types represented more than 75% of the patients, including non-small cell lung cancer (27%), colorectal (19%), breast (13%), pancreatic (8%) and gastric (8%) cancers. Known or suspected deleterious BRCAm was observed in 4.6% of patients across tumors and varied by tumor type, with the highest prevalence in ovarian cancer (13.0%). Total HRRm prevalence was 13.2% across tumor types with prostate cancer (25.9%) as the highest, and the prevalence of HRD+ was 20.6% cross tumor types with breast cancer (34.4%) as the highest. The adjusted hazard ratio (aHR) for OS from initiation of 2L therapy for patients with BRCAm vs BRCA wild type (BRCAwt) was 0.81 (95%CI, 0.61-1.07). Comparable results were observed when calculating OS from 1L or 3L therapy. The aHR of OS from 2L therapy with HRRm vs HRRwt was 0.92 (0.78-1.09) and 1.20 (1.01-1.43) for patients with HRD+ vs HRD negative (HRD-). Conclusions: The prevalence of BRCAm, HRRm, and HRD+ varies widely by tumor type. There was no association between BRCA/HRRm status and OS, yet HRD+ might be associated with shorter OS among patients who were not treated with PARPi or IO across the evaluated tumor types.[Table: see text]
Breakthrough COVID-19 cases and hospitalization risk: ASCO COVID-19 registry.
Authors: Bruinooge Suanna Steeby , Kurbegov Dax , Kaltenbaugh Melinda , Hanley Williams Jen Hanley , Gralow Julie R. , Garrett-Mayer Elizabeth 
Published: June 2022

e18807 Background: The ASCO Registry was created to analyze the impact of COVID-19 (COVID) on treatment (Tx) and outcomes of patients (pts) with cancer. Vaccination questions were added in 2021, enabling examination of breakthrough cases  i.e., SARS-CoV-2 infection after vaccination. Methods: The Registry includes pts who test positive for SARS-CoV-2 and have clinically evident cancer receiving Tx or resected cancer on adjuvant Tx <12 months since surgery at the time of the positive test. Practices report data on COVID vaccine type and dates, positive SARS-CoV-2 test date, and subsequent Tx. Breakthrough cases were defined as 1) > 35 days after 1st Pfizer dose, 2) > 42 days after 1st Moderna dose, 3) > 14 days after 1st Janssen dose, or 4) > 42 days after 1st unknown vaccine dose. Data submission cutoff for all practices was February 2, 2022. Summary statistics and exact binomial 95% confidence intervals (CIs) were calculated. Results: This analysis reports on 231 pts with breakthrough cases. Median age is 68 years and 57% of pts are over age 65. Of 73 pts with non-metastatic solid tumors, 19% were hospitalized. Of 74 with metastatic solid tumors, 39% were hospitalized. Of 75 with B-cell malignancies, 32% were hospitalized. Of 9 with other hematologic malignancies, 56% were hospitalized. While the fraction of patients in the ASCO registry with breakthrough cases who were hospitalized remained fairly constant throughout 2021 (approximately 40%), those with breakthrough cases occurring in the last month of 2021 and early 2022 had a lower hospitalization rate (approximately 20%), which is consistent with less severe cases of COVID-19 in patients infected with the omicron variant (the predominant variant in the US in Dec 2021- Jan 2022) (Table). The majority of breakthrough cases occurred more than 6 months after initial vaccination (71%) and the median time to breakthrough infection from initial vaccination was 7.3 months (IQR: 5.6  9.9). The Registry continues to accrue cases and additional vaccine data; analysis will be updated with most current vaccination data for possible Annual Meeting presentation. Conclusions: Hospitalizations among patients with cancer and breakthrough COVID in the ASCO Registry occur at a high rate, particularly among patients with advanced cancers and hematologic malignancies. This decrease in recent months is likely due to increased incidence of the Omicron variant that resulted in milder COVID symptoms among those infected. A majority of SARS-CoV-2 infections occurring six months or more after vaccination suggests waning vaccine efficacy over time that could be impacted by additional doses.[Table: see text]
Real-world healthcare resource utilization and costs among patients with multiple myeloma in the United States.
Authors: Gupta Niodita , Tai Ming-Hui , Kaila Shuchita , Thompson-Leduc Philippe , Ghelerter Isabelle , Kurteva Siyana , Lefebvre Patrick , Lafeuille Marie-Hélène 
Published: June 2022

e18811 Background: The economic burden of multiple myeloma (MM) has been shown to increase with more advanced lines of therapy (LOTs). Given the rapidly evolving treatment landscape of MM, this study aimed to describe the current real-world healthcare resource use (HRU) and costs among patients with MM across LOTs. Methods: A commercial insurance claims database was used to identify patients with ≥2 MM diagnoses who initiated a LOT containing an antineoplastic agent for MM between 1/2016 and 2/2021, had continuous insurance coverage ≥6 months before and ≥60 days after first line (1L) initiation, and never received stem cell transplant. LOTs were defined based on agents used within a 60-day period. End of LOT was defined when patients switched treatment, or after a treatment gap of 90 days. HRU and costs (in 2021 USD) were reported for the duration of each LOT (from initiation of LOT to initiation of a subsequent LOT or end of coverage). Results: 1492 patients initiated 1L, 681 initiated 2L, 359 initiated 3L and 188 initiated 4L. Mean age at 1L initiation was 66.6 years. Mean duration of LOT (10.7, 9.4, 8.1 and 10.2 months in 1L, 2L, 3L and 4L, respectively) was longer in 1L than in subsequent LOTs. All-cause monthly outpatient (OP) and inpatient (IP) visits were stable across LOTs (5.0-5.6 OP visits; 0.21-0.32 IP visits). However, mean monthly all-cause costs were lowest in 1L (15.9% - 34.9% lower) as compared to subsequent LOTs ($23.6K in 1L, $29.7K in 2L, $27.3K in 3L and $31.8K in 4L; Table). Conclusions: In this study, the duration of LOT was the longest among 1L patients. Total all-cause healthcare costs were the lowest in 1L than in more advanced LOTs. This suggests that selection of 1L best treatment regimen upfront that prolongs time to disease progression could reduce the overall economic burden of MM.[Table: see text]
Impact of preauthorization review on oncology drug and radiation costs.
Authors: Talcott James Austin , Salmon-Gardell Megan , Kozlovsky Vlad , Yedwab Erik , Boehringer Traci , Avery Tiffany P. 
Published: June 2022

e18829 Background: Preauthorization review (PR) is designed to ensure that patients receive evidence-based medicine (EBM) treatment but also affects costs. We estimated changes in chemotherapy and radiation costs when PR found treatments to deviate from EBM. Methods: We identified chemotherapy and radiation treatment plans reviewed by Eviti Connect in 2020 found to contain medically unjustified deviations from EBM after a request for peer-to-peer discussion. We calculated the cost difference in antineoplastic and supportive drugs and radiation procedures between deviating plans and any approved replacements. We assumed completion of curative drug regimens and 4 months duration for non-curative treatments. Results: We report net change in treatment costs for all patients with plans reviewed. Of 13,370 patients with reviewed plans, 1-4 deviating plans were identified for 1899 patients (14.2%), or 2160 deviating plans. Mean savings were $38,242 (95%CI $35,354 - $41,118) per patient with a deviating plan, $33,097 (95%CI $30,851- $35,343) per deviating plan, and $5,348 per patient with a plan reviewed. Inflation-adjusted per patient savings were 27% greater than we reported in 2012. Total savings were $71,497,374. Applying these results to a covered population of 1 million, assuming 0.3% undergo PR annually, would save $16,041,000. Provider appeals were submitted for 2.2% of cases found deviating and 0.3% were upheld. Conclusions: PR directly ensures EBM cancer care by identifying deviating treatments and reduces treatment costs. This analysis likely underestimates realized savings because it includes only drug and radiation procedure costs; noncurative treatments often extend beyond 4 months; and provider experience with PR may deter submitting treatments previously determined to be deviating.
Treatment patterns and medical costs of metastatic breast cancer care in the United States.
Authors: Jaber Chehayeb Rachel , Hood Annette , Mougalian Sarah Schellhorn , Lustberg Maryam B. , Wang Shi-Yi , Greenup Rachel Adams , Pusztai Lajos , Kunst Natalia 
Published: June 2022

e18834 Background: Substantial advances in treatment of metastatic breast cancer (mBC) have led to changes in clinical practice and treatment costs in the United States in the past decade. We aimed to identify treatment patterns in mBC patients by subgroup and year after mBC diagnosis and associated costs from payer and societal perspectives. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database (1/2011-5/2021). We excluded cases that were male, had < 6 months of follow up, no treatment data, no structured data within 90 days of diagnosis, participated in clinical trials, had non-breast invasive cancers, received therapies not used in mBC, had no data on human epidermal growth factor (HER2) and hormone receptor (HR) status. We classified patients into four subgroups: HER2-HR+, HER2+HR+, HER2+HR-, and Triple Negative (TNBC). We calculated anti-cancer and supportive drug costs at the patient level and mean costs by year after diagnosis for each subgroup. We used average wholesale prices (AWP, from McKesson Corporation) for payer perspective and Medicare prices (part B payment limit data, Part D Drug Spending Dashboard) for societal perspective. We estimated costs up to year 5 after diagnosis of mBC (< 8% received treatment after year 5). Results: 15,215 patients met the criteria (64.41% non-Hispanic White, 66.85% HER2-HR+, 18.30% HER2+HR+, 5.27% HER2+HR-, 9.58% TNBC). AWP and Medicare cost estimates by year after diagnosis and subgroup are shown in Table. 334,812 for HER2+HR+, $284,609 for HER2+HR-, $104,774 for HER2-HR+, and $54,355 for the TNBC. We observed an increase in annual costs between years 2011-2021 in most subgroups. This increase was most substantial for HER2-HR+ patients. From 2011 to 2019 (most recent complete year 1 data is for patients diagnosed in 2019), annual Medicare treatment costs in year 1 increased from $12,986 to $80,563 for HER2-HR+, $99,997 to $156,712 for HER2+HR+, and $31,397 to $53,775 for TNBC. There was no increase in costs of treating HER2+HR- in year 1, but an increase in year 2 (from $90,427 to $129,690 between 2011-2019). Conclusions: mBC treatment costs vary significantly by receptor subtype and years after diagnosis. Annual costs increased over time. Costs were greatest for HER2+ and lowest for TNBC.[Table: see text]
Determination of direct treatment costs of patients with metastatic and nonmetastatic castration-resistant (mCRPC, nmCRPC) and metastatic hormone-sensitive (mHSPC) prostate cancer in Colombia.
Authors: Niño Rafael , Restrepo-Miranda Diego , Amezquita Miguel Alberto , Lancheros Jeisson , Corredor Lina Maria , Medina Yudy , Aguirre Andres 
Published: June 2022

e18838 Background: The purpose of this study was to determine the direct costs associated with the management of patients with metastatic castration resistant (mCRPC), non-metastatic (nmCRPC) and metastatic hormone-sensitive (mHSPC) prostate cancer in the Colombian healthcare system. Methods: First, a literature review was carried out to identify the main clinical recommendations for the treatment and follow-up of patients with prostate cancer at local and international levels. Subsequently, a participation process was developed with clinical experts, through a modified Delphi panel, to validate the natural history of the disease, and identify treatment options, skeletal-related events management, resource utilization, and distribution of patients within stages. Based on the above, a cost analysis model was performed, using Colombian health technology assessment agency recommendations, to calculate direct cost of treatment for mCRPC, nmCRPC and mHSPC from payer’s perspective. Exchange rate used was USD $1 = COP $4,000. Finally, the results were estimated considering the cost per patient per year. Results: According to the cost analysis of each stage, in the non-metastatic castration resistant stage (nmCRPC) the associated yearly cost of a patient was lower than in the metastatic castration resistant stage (mCRPC) (USD $8,581 versus $24,590, respectively), with a difference of USD $16,008. The metastatic hormone-sensitive stage (mHSPC) had a lower yearly cost than the metastatic castration-resistant stage (mCRPC) (USD $15,030 versus $24,590, respectively), with a difference of USD $ 9,559. The event that generated the greatest impact on the cost is the incidence of skeletal-related events associated with disease metastasis (55%). The deterministic sensitivity analysis on key variables, such as the percentage of patients who responded to treatment and the incidence of skeletal-related events, showed consistency of results. Conclusions: Delaying or stopping disease progression to mCRPC could more than halve annual treatment costs for patients. Given the findings, advanced metastatic castration resistant stages demand more resource utilization associated with disease management. The Colombian healthcare system would benefit from risk management strategies that implement timely interventions associated with early diagnosis and screening. In this way, the resource utilization in health sector's institutions would be directly impacted through budget optimization, obtaining better results focused on the national follow-up indicators of the prostate cancer patient cohort.
Cyclin-dependent kinase 6 body methylation and association with prognosis of patients with acute myeloid leukemia.
Authors: Zhang Lei , Ma Rui , Yu Qingxiang , Sun Lihua 
Published: June 2022

e19000 Background: Cyclin-dependent kinase 6 (CDK6) plays critical roles in leukemogenesis and leukemia stem cells activation, and its inhibition has emerged as a novel therapeutic strategy in acute myeloid leukemia (AML) management. However, association between CDK6 methylation and prognosis in patients with AML remains unclear. Methods: Methylation profile, somatic alterations, and CDK6 gene expression data of 200 clinically annotated patients with de novo AML were retrieved from the TCGA Pan-Cancer Atlas project deposited in the UCSC Xena database. Specifically, methylation levels of all 64 CpGs across CDK6 were extracted, and then methylation abundances of promoter and gene body regions were calculated as average levels of CpGs located in the respective regions. Patients were categorized into two subgroups (hypo- and hyper-methylated) as per the median methylation level for either region or single CpG site. Log-rank tests were conducted to compare overall survival (OS) of patients stratified by methylation status. A Cox proportional hazards model was fitted to control confounding factors, including age, white blood cell count, cytogenetic risk classification (favorable, intermediate, and poor risk), and TP53 mutations, as reported previously. Associations of methylation status with cytogenetic risk and somatic alterations were examined using the Wilcoxon and Kruskal-Wallis rank sum tests, respectively. Spearman rank correlation coefficient ( R) was used to evaluate correlations between methylation and expression. Results: Of the 200 patients, 109 (54.5%) were men, and median (interquartile range [IQR]) age was 57.5 (44.75-67) years. Median (IQR) methylations of promoter and body were 5.2% (4.8%-5.7%) and 55.6% (53.7%-57.9%), respectively. Body methylation was observed to correlate with gene expression ( R, -0.22; P = .005), but not promoter methylation. In Kaplan-Meier analysis, low methylation of body rather than promoter predicted prolonged OS (median, 27.4 vs 9.2 months; hazard ratio [HR], 0.43; 95% CI, 0.29-0.63; P < .001). Notably, the OS improvement persisted with multivariable Cox model adopted (HR, 0.64; 95% CI, 0.42-0.98; P = .038). In addition, the body hypomethylation was strongly associated with early age, favorable cytogenetic risk, mutations in TP53, NPM1, and IDH1/ 2, as well as PML- RARA and MYH11- CBFB fusions (all P < .05). Further analysis identified that cg08300570, cg09653641, cg10481072, and cg13590558 in the body were all prognostic for OS (all P < .05). Intriguingly, all these CpGs resides in the enhancer. Conclusions: This is the first study to unravel clinical significance of CDK6 body methylation in AML, and it may serve as an independent prognostic marker. Given that azacitidine and decitabine are widely used, our findings may have implications for combination therapy of CDK4/6 inhibitors with hypomethylating agents in AML. Prospective studies are warranted.
Clinicopathologic characteristics and treatment outcomes of de novo myeloid sarcoma.
Authors: Kuhlman Justin J. , McCormick Benjamin J. , Badar Talha , Foran James M. , Abdel Rahman Zaid H. , Murthy Hemant S. 
Published: June 2022

e19002 Background: Extramedullary disease in acute myeloid leukemia (AML), also known as myeloid sarcoma (MS), is an uncommon presentation of de novo AML. Clinicopathologic characteristics and optimal treatment strategies of de novo MS remain unclear in both isolated MS without bone marrow (BM) involvement and synchronous MS with BM involvement. Methods: In a single-site retrospective study, medical records of patients with de novo extramedullary AML who received oncological care at any Mayo Clinic site between 1996 and 2021 were analyzed. Using BlueSky Statistics software, survival outcomes were analyzed using Kaplan-Meier and Cox-proportional hazard models for univariate and multivariate analysis, respectively. Results: 83 patients with de novo MS were identified; 49 (59%) presented with synchronous MS and 34 (41%) exhibited isolated MS. Median age at diagnosis was 56 years (range, 17-89); 63% were male. Next-generation sequencing of the blood +/- BM revealed abnormalities in 24/27 (88%) analyzed patients; aberrations included mutations in RTK-RAS pathways (12/27), NPM1 (10/27), TET2 (6/27), and IDH2 (4/27). Median length of follow-up was 1.73 years (95% CI; 0.03-3.0); 53 patients (64%) had expired. Median event free survival was 0.64 years and 0.61 years in isolated and synchronous MS, respectively (p = 0.5). Median overall survival (mOS) in isolated and synchronous MS was 2.1 years and 1.5 years, respectively (p = 0.5). Induction treatment with intensive chemotherapy (IC) was administered in 70 patients (84%). IC regimens included 7+3, MEC, CLAG-M, and hyper-CVAD. Variables associated with improved survival in both groups included treatment with IC +/- allogenic stem cell transplant (alloSCT) (p < 0.001), normal or favorable risk karyotype (p = 0.001), and age less than 60 (p = 0.001). Localized therapy (LT) did not provide an added survival benefit. Patients with synchronous MS were more likely to relapse in the BM and blood than isolated MS (p = 0.02). Conclusions: Enriched with RTK-RAS mutations, de novo MS remains an aggressive form of AML, particularly in patients with intermediate or high-risk genomics or those with skin, soft tissue, or lymphatic involvement. IC should be employed with consideration of alloSCT in eligible patients, particularly in synchronous MS due to a heightened risk for medullary and leukemic relapse.[Table: see text]
Beyond gemtuzumab ozogamicin: A systematic review of antibody therapies for acute myeloid leukemia.
Authors: Sumbly Vikram , Landry Ian , Iqbal Qamar , Rehman Mohammad Ebad Ur , Chattaraj Asmi , Aijaz Zobia , Khattak Zoia Ehsan , Anwer Faiz 
Published: June 2022

e19006 Background: Acute myeloid leukemia (AML) is a neoplasm that is defined by the uncontrolled growth of myeloid progenitor cells. It is the most common form of acute leukemia in adults and is associated with poor outcomes in patients ≥ 75 years. Multiple antibody-drug conjugates (ADCs) are being investigating for their benefits in AML. Methods: A search was performed on PubMed, Cochrane, Scopus, Web of Science and ClinicalTrials.gov using the PRISMA guidelines. After screening 1,806 articles, a total of eight studies were included for this review. Results: Montesinos et al. gave a combination of talacotuzumab (anti-CD123 antibody) + decitabine to AML patients and reported an ORR of 27% (42/157) in the talacotuzumab + decitabine arm. Uy et al. studied flotetuzumab (anti-CD3 x anti-CD123 DART) and reported an ORR of 30% (9/30) in patients treated at the recommended phase two dose. Ho et al. noticed a CR in 26% (30/117) of patients who received a combination of vadastuximab talirine (anti-CD33 ADC) with azacytidine/decitabine. Feldman et al. observed that the ORR was higher in the lintuzumab (anti-CD33 antibody) + chemotherapy arm than control arm (36% vs 28%). Daver et al. and Vey et al. both studied lirilumab (anti-KIR antibody), but Daver et al. reported an ORR of 14% (5/32) in the lirilumab + azacytidine arm. In a separate study, Daver et al. administered nivolumab (anti-PD1 antibody) + azacytidine and noticed an ORR of 33% (23/70). Zeidan et al. reported that the durvalumab (anti-PD-L1 antibody) + azacytidine arm had a lower ORR than the control arm (31% vs 35%). A summary of the adverse events was provided below (Table). Conclusions: Antibody-based therapies are showing great promise for the treatment of AML but are associated with various adverse effects. More prospective clinical trials are needed to further assess the long-term benefits of such medications.[Table: see text]