bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of FOXC1 expression as a predictor of response to neoadjuvant taxane plus platinum regimens in primary triple-negative breast cancer: Retrospective analysis of three clinical trial cohorts.
Authors: Ray Partha , Ray Tania , Lopez-Tarruella Cobo Sara , del Monte Millan Maria , Álvarez Enrique , Jerez Gilarranz Yolanda , Roche Marta , Taylor Clive R. , Martin Miguel
Published: June 2022

569

Background: Taxane and platinum (TP) NAC regimens, e.g. Carboplatin and Docetaxel (CbD), in TNBC are currently of great interest, having good pathologic complete response (pCR) rates but with a significantly more manageable toxicity profile compared to anthracycline-based NAC regimens. Forkhead Box C1 (FOXC1), a transcriptional driver of cell plasticity/partial EMT/metastasis is an established mesenchymal marker diagnostic of basal-like breast cancer having proven prognostic value, but of uncertain predictive value. We sought to evaluate the potential of FOXC1 in predicting pCR to neoadjuvant TP regimens in patients diagnosed with TNBC. Methods: Pre-NAC tumor biopsy FOXC1 mRNA expression status was correlated with rate of pCR in a pooled, ambispective cohort (prospective cohort GEICAM/2006-03, NCT00432172 pooled with multi-institutional retrospective cohort, n = 119). A specific FOXC1 mRNA expression cutoff value was derived to maximize Negative Predictive Value (NPV) and Sensitivity for pCR prediction. The pCR-predictive ability of FOXC1 mRNA expression was then assessed in two validation cohorts of evaluable patients who had been enrolled in prospective clinical trials (UCONN/FIOCRUZ, n = 222, HGUGM, NCT01560663, n = 221). All evaluated patients had been diagnosed with TNBC and had received a Taxane plus Platinum-based NAC regimen. Results: FOXC1 mRNA expression was associated with pCR in CbD/TP treated TNBC patients with pCR rates of 43.48%, 47.89% and 52.73% observed in the discovery and two validation cohorts (two tailed T-test p-values of 0.0005, 0.002, 0.009, respectively). FOXC1 expression above the pre-determined cutoff value was associated with pCR to CbD/TP NAC in patients diagnosed with TNBC in both validation cohorts (OR 4.894, 1.504-15.924; p = 0.004 and OR 2.293, 1.208-4.352; p = 0.006). Conclusions: We report the retrospective validation of pre-NAC breast cancer biopsy FOXC1 mRNA expression for predicting efficacy of CbD/TP NAC in two independent, prospectively accrued TNBC patient cohorts. The described strategy may be acceptable for patient stratification to guide CbD/TP NAC recommendations in TNBC. FOXC1 mRNA or protein expression, assessed using qRT-PCR or routine immunohistochemistry (IHC), respectively, could potentially be utilized in future fixed-arm/adaptive clinical trials to further optimize NAC efficacy, in terms of achieved pCR rates, and to extend disease-free survival in patients diagnosed with TNBC.
miR-150 expression in breast cancer attracts and activates immune cells, and is associated with better patient outcome.
Authors: Oshi Masanori , Maiti Aparna , Wu Rongrong , Tokumaru Yoshihisa , Murthy Vijayashree , Yan Li , Ishikawa Takashi , Endo Itaru , Hait Nitai , Takabe Kazuaki
Published: June 2022

570

Background: MicroRNA (miRNA) epigenetically regulate a large number of cancer-related genes and is known as a key player in cancer biology. MiR-150 promote cancer cell proliferation, migration, and invasion. However, there has been no study that investigated the role of miR-150 in the tumor microenvironment (TME) of breast cancer patients. Methods: Total of 1,961 breast cancer patients from multiple independent large cohorts were analyzed. These observational results were validated by in vitro experiments. Lymphocyte attraction was assessed using Transwell system. Results: miR-150 expression was the highest in triple negative breast cancer (TNBC) among subtypes and correlated with Nottingham histological grade (all p<0.001). A high miR-150 was significantly associated with better overall survival (OS) in both METABRIC and TCGA cohorts regardless of subtypes (all p<0.05 except for TNBC in TCGA). MiR-150 expression was strongly correlated with Hallmark immune-related gene sets (Allograft rejection, IL6 signaling, IFN-γ response, Inflammatory response, IL2 signaling, and apoptosis), with cytolytic activity, with infiltration of CD8+ T cells, CD4+ memory T cells, and dendritic cells, as well as with gene expressions of major immune checkpoint molecules (PD-1, CTLA4, IDO1, TIGIT, BTLA, and LAG3), consistently in both METABRIC and TCGA cohorts (all r>0.65, p<0.01). Unexpectedly, overexpression of miR-150 by mimic did not increase growth, migration, nor invasion of neither MDA-MB231 or BT-549 breast cancer cell lines. On the other hand, overexpression of miR-150 in either MDA-MB231 or BT-549 significantly increased attraction of lymphocyte cell line (Jurkart cells), which was abolished by addition of miR-150 inhibitor. By comparing the gene expression profile between miR-150 overexpressed and control cells, we found that many inflammation related gene sets including NF-kB signaling that enhance cell migration was enriched to miR-150 overexpressed cells, implicating that is how miR-150 high cells attract lymphocytes to TME. Conclusions: miR-150 expression is associated with immune cell infiltration and immune response, as well as with better survival in breast cancer patients. Overexpression of miR-150 in breast cancer cells did not promote cancer cell proliferation, migration, nor invasion; however, increased attraction of lymphocytes. Multiple inflammation-related genes were expressed higher in miR150 overexpressed MDA-MB231.
Three-year disease-free survival in randomized trials of chemotherapy and HER2-targeted therapy: A meta-analysis.
Authors: Mittal Abhenil , Tamimi Faris , Molto Consolacion , Meti Nicholas , Al-Showbaki Laith , Wilson Brooke , Amir Eitan
Published: June 2022

579

Background: The Katherine trial reported a 3-year invasive disease-free survival (DFS) of 77% in patients not achieving pathological complete response (pCR) and continuing on adjuvant trastuzumab. Case series suggest better outcomes and data support that some patients with residual disease have similar outcomes to those with pCR (Steenbruggen et al). The absolute benefit of adjuvant trastuzumab emtansine (T-DM1) would be smaller in patients with favourable outcomes despite residual disease. As such, a more precise estimate of 3-year DFS is needed for treatment planning. Methods: We reviewed reports of randomized trials of neoadjuvant chemotherapy and HER2-directed therapy and extracted the 3-year DFS, a validated surrogate endpoint in HER2-positive early-stage breast cancer. Data were extracted for patients with residual disease and with pCR. The mean 3-year DFS weighted by study sample size was calculated. Meta-regression comprising linear regression weighted by sample size (mixed effects) was performed to explore associations between 3-year DFS and trial-level patient, disease and treatment factors and changes in 3-year DFS over time. Quantitative significance was explored using methods described by Burnand et al. Results: Eleven studies comprising 3908 patients were included in the analysis. The mean 3-year DFS for patients with pCR and for residual disease was 90.1% and 80.0%, respectively. DFS improved over time. For trials whose final year of accrual was after 2010, mean 3-year DFS for residual disease was 84.7% compared to 78.0% for trials completing accrual before that time (p<0.001). In a subgroup analysis of patients with residual disease, those receiving dual HER2-targeted therapy in the neoadjuvant setting had a 3-year DFS of 85.3% compared to 73.3% for those receiving only trastuzumab (p<0.001). Meta-regression results for residual disease are shown in the Table. Positive quantitative significance was observed for final year of accrual, ER-expression, dual anti-HER2 therapy and concurrent vs sequential anti-HER2 therapy. Negative quantitative significance was observed for larger clinical tumor size and nodal involvement. Conclusions: 3-year DFS for patients with residual disease and HER2-targeted therapy is better than reported in the Katherine trial and has improved over time, possibly due to increased use of dual HER2-targeted therapy in the neoadjuvant setting. In this context, the absolute benefit of adjuvant T-DM1 may be smaller than anticipated. [Table: see text]
Dapagliflozin associated to sacubitril/valsartan and relationship with cardioprotection in human cardiac cells exposed to doxorubicin and HER2-blocking agents through MyD88, NLRP3 mediated pathways.
Authors: Maurea Nicola , Quagliariello Vincenzo , Iovine Martina , Buccolo Simona , Paccone Andrea , Bisceglia Irma , De Laurentiis Michelino
Published: June 2022

587

Background: The cumulative incidence of cardiac events in breast cancer patients treated with anthracycline and trastuzumab at 1 year after the diagnosis of cancer was 16.4%, at 2 years 23.8 %, and at 3 years 28.2%. Sodium glucose co-transporter 2 inhibitors, a new class of antidiabetic drugs, has shown measurable benefits in reduction of HF hospitalization and cardiovascular mortality. LCZ696 (neprilysin inhibitor + valsartan) as able to lower the risk of cardiovascular events in chronic heart failure. We hypothesize that dapagliflozin associated to LCZ696 could exerts cardioprotective effects in cellular models of doxorubicin and trastuzumab-induced cardiotoxicity. Methods: Human cardiomyocytes (HL-1 cells) were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin (50 nM) or LCZ696 (at 100 mM) or both in combination for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of malondialdehyde, 4-hydroxynonenal and intracellular Ca2+ were performed through spectrophotometric methods. Anti-inflammatory studies were also performed (expression of NLRP3 inflammasome, TLR4/MyD88 pathways, nuclear expression of NF-kB). Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF were also performed. Results: Dapagliflozin and LCZ696 increased synergistically the cell viability during exposure to doxorubicin and trastuzumab. Combination of dapagliflozin and LCZ696 reduces intracellular Ca2+ overload (-68,4% vs cells treated only to anticancer drugs; p<0,001), lipid peroxidation (mean reduction of 57-63,4 % compared to cells exposed only to anticancer drugs; p<0,05). The expression of MyD88, NLRP3 and NF-kB were strongly reduced after treatment with dapagliflozin and LCZ-696 (-52,5, -43,7 and -57,3 % vs cells exposed only to anticancer drugs, respectively; p<0.05). Notably, combination of dapagliflozin and LCZ-696 enhanced the expression Of IL-10; contrary, pro-inflammatory cytokines were reduced, such as IL-1α, IL-1β, IL-6, IL-8, IL17-α and IL-18 (p<0.05). Conclusions: During exposure to doxorubicin and trastuzumab, dapagliflozin associated to LCZ-696 exerts additive cardioprotective and anti-inflammatory effects compared to each drug alone. Their properties are mediated by the reduction of iCa2+ content that consequently reduces peroxidation and NLRP3- MyD88 expression. These results indicating the potential use of SGLT-2 inhibitors associated to LCZ696 in preclinical models of cardiotoxicity.
Prediction of response to neoadjuvant therapy (NAT) in early breast cancer (EBC) at community hospitals: SimBioSys TumorScope Validation Study.
Authors: Pfeiffer John R. , Zwicky Karen , Pandey Tushar , Antony Anu K. , Team The SimBioSys , Cole John A. , Wolf Clifford
Published: June 2022

598

Background: While most cancer patients are treated at community hospitals, specialized equipment, diagnostic tests, and therapeutic regimens are generally validated at academic settings. Here we present a novel approach to precision medicine to improve outcomes in breast cancer care in the community setting. TumorScope (TS) is a biophysical modelling platform that uses only pretreatment standard of care (SoC) diagnostic data (demographics, drug regimen, imaging (DCE MRI) & pathology) to construct a 3D model of the tumor. TS integrates models for tumor morphology, metabolism, vascularity, and drug behavior and simulates predicted tumor response longitudinally to NAT. With this information TS predicts the reduction in tumor volume and the pathological complete response (pCR), a surrogate marker of long-term outcome, to anticipated NAT in EBC. Methods: We performed a single center validation study to show the clinical applicability of TS. Patients at Northwest Community Healthcare that received NAT with corresponding pretreatment MRI were identified in a chart review. A validation set, independent from the training set, was generated from this list and data processed through TS (n=50). Pretreatment patient SoC diagnostic data was loaded into TS. TS predicted the weekly volumetric response throughout the treatment, and it simulated residual volume to predict pCR. The validation was performed using ground truth from post treatment assessment of pCR, radiographic volumes extracted from MRIs. Results: TS predicted pCR, prospectively defined as a simulated residual tumor volume <0.01 cm3 or a 99.9% or greater reduction in tumor volume. Performance metrics of TS were calculated. TS tumor volume prediction accuracy had an area under the curve (AUC)=0.947 with sensitivity and specificity of 93.3% and 94.3% respectively. Performance was robust across all subtypes (See Table 1). TS predicted the reduction in tumor volume with a median absolute volumetric error of 3.4% as compared to radiographic volume from pre-surgery MRIs (n=50). Conclusions: In summary, TS accurately predicts patient-specific tumor volume reduction and pCR prior to NAT in EBC using only SoC pretreatment data, which could lead to a more personalized cancer care for the patient. Moreover, we demonstrate the feasibility of implementing TS at community hospitals. [Table: see text]
Deep learning algorithm to predict pathologic complete response to neoadjuvant chemotherapy for breast cancer prior to treatment.
Authors: Choi Rachel , Joel Marina , Hui Miles , Aneja Sanjay
Published: June 2022

600

Background: Pathologic complete response (PCR) to neoadjuvant chemotherapy (NAC) is associated with improved disease-free survival and overall survival in patients with breast cancer. Predicting PCR at the patient level prior to treatment initiation would allow physicians and patients to focus on therapies with the highest likelihood of success and minimize unnecessary toxicities from chemotherapy. We hypothesize that pre-treatment prediction of PCR is possible through a deep neural network algorithm trained on breast MRI imaging obtained prior to treatment. Methods: 126 tumors from patients treated with neoadjuvant chemotherapy for T3 stage breast cancer at a single institution from 2002 to 2006 were analyzed. In total, 3780 MRI slices were included. 3 MRI contrast phases (pre, immediate post, delayed post) from each slice were used as individual inputs to create separate model predictions of PCR. The 2-D CNN was trained over 50 epochs on the training set. The model was tested on the isolated test set (30% of samples). Results: Average model prediction accuracy over the total test set using a single phase of contrast (pre-, immediate post-, or delayed post-) was 90.4%. Concordance adjustment was conducted, with exclusion of slices that had produced discordant predictions across different contrast phase inputs. This resulted in an increase of overall model accuracy to 97.6%. Model accuracy was similar across subsets of age and tumor size despite differences in PCR rates. However, model accuracy was significantly lower in the triple-negative disease group. Conclusions: We demonstrate a deep neural network that accurately predicts PCR based on breast MRI imaging taken prior to NAC initiation. Our findings represent the promise of deep learning algorithms in providing personalized prognostic data for physicians and patients. [Table: see text]
Association of Medicaid expansion under the Affordable Care Act and overall survival among children with cancer.
Authors: Barnes Justin Michael , Neff Corey , Kruchko Carol , Barnholtz-Sloan Jill , Ostrom Quinn T , Johnson Kimberly J.
Published: June 2022

6507

Background: State Medicaid expansions under the Affordable Care Act are associated with increased Medicaid coverage among children, including those with cancer. Since the expansions did not directly affect Medicaid eligibility criteria for children, these changes suggest “welcome mat” effects, where previously uninsured children become enrolled in Medicaid after their parents gain coverage. Insurance improvements from the expansions have been associated with improved cancer outcomes for non-elderly adults. However, it is unclear whether the expansions also impacted childhood cancer outcomes. Methods: Data for children ages 0-14 years diagnosed with cancer from 2011-2017 were queried from central cancer registries covering cancer diagnoses from 43 states as part of the Centers for Disease Control’s National Program of Cancer Registries. The primary outcome was 2-year overall survival. We utilized difference-in-differences analyses to compare changes in 2-year survival from 2011-2013 to 2014-2017 between children who resided in states expanding Medicaid by 2014 vs. states not expanding Medicaid within the study period. Analyses were adjusted for covariates including age, race/ethnicity, sex, metropolitan residence, cancer type, and stage at diagnosis. Results: A total of 42,970 children with cancer were included. Overall, there were increases in 2-year survival among children in expansion states (90.5% in 2011-2013 to 91.4% in 2014-2017) but no change among children in non-expansion states (90.0% in 2011-2013 to 90.0% in 2014-2017). In adjusted difference-in-differences analyses, there was no significant change in survival after Medicaid expansion for children in expansion vs. non-expansion states (1.01 percentage points, 95% CI = -0.23 to 2.25, p = 0.11). In difference-in-differences analyses by race/ethnicity, there was a significant expansion-associated improvement in survival in Black children (3.97 percentage points, 95% CI = 0.02 to 7.93, p = 0.049) but not in White children (0.4 percentage points, 95% CI = -1.07 to 2.04, p = 0.54). There were also expansion-associated improvements in survival among children residing in counties with the lowest quartile of county income (5.88 percentage points, 95% CI = 0.38 to 11.38, p = 0.036) but not for those in higher income counties (1.15, 1.23, and 0.12 percentage points for 2nd, 3rd, and 4th quartiles, respectively). Conclusions: Medicaid expansion, through presumed increases in Medicaid coverage via welcome mat effects, was associated with increased 2-year survival for Black children and children residing in low-income counties. However, the concentration of Black children in states that have not expanded Medicaid highlights the need for further advocacy to more fully achieve improved outcomes. Future data are needed to clarify potential long-term impacts of Medicaid expansion on childhood cancer outcomes.
Associations between interpersonal violence and cancer risk factors for transgender and cisgender people.
Authors: Alpert Ash B. , Sayegh Sabrina Jamileh , Strawderman Myla S. , Cunliffe Scott , Cupertino Ana Paula , Griggs Jennifer J. , Cerulli Catherine
Published: June 2022

6516

Background: Cancer risk factors for transgender people are largely unexplored. Extreme rates of interpersonal violence experienced by transgender people may increase the risk of cancer. The associations between exposure to interpersonal violence and cancer risk factors have not been investigated. Methods: We searched for experiences of violence in cohorts of 923 transgender and 1846 cisgender people matched by age, follow-up time, and year of the first encounter and measured the association between these experiences and smoking as well as BMI ≥ 40. We then estimated the prevalence ratios for these risk factors using robust Poisson regression models including gender identity, violence, and their interaction, adjusted for age and follow-up time. Results: Transgender people experienced more violence than cisgender people. Among transgender people, there were significantly higher rates of smoking among those who had experienced any type of violence (50% vs 35%, p<.0001) and borderline significantly higher rates of BMI ≥ 40 (23% vs 18%, p=.05). Among cisgender people, significantly higher rates of smoking in those who had experienced violence (52% vs 31%, p<.0001) and significantly higher rates of BMI ≥ 40 (23% vs 11%, p<0.001) were also demonstrated. No statistically significant difference was demonstrated in the association between violence and smoking in transgender compared with cisgender people (prevalence ratio (PR).87, p=.17). A statistically significant difference was demonstrated in the association between violence and BMI ≥ 40 in transgender compared to cisgender people (PR.65, p=.02). Conclusions: Given the association between violence and cancer risk factors, eliminating violence is of profound concern to the oncology community. Violence across the life course is markedly higher in transgender versus cisgender people. Interventions are urgently needed to eliminate violence. Cancer prevention research should investigate the efficacy of methodologies known to impact interpersonal violence, including those modifying structural factors to decrease socioeconomic disparities, stigma, and oppression. [Table: see text]
Real-world progression-free survival (rwPFS) and time to next line of therapy (TTNT) as intermediate endpoints for survival in metastatic breast cancer: A real-world experience.
Authors: Labaki Chris , Bakouny Ziad , Sanglier Thibaut , Schmidt Andrew Lachlan , Shim Jinjoo , Braun David A. , Bouquet Fanny , Joyce Maureen Ann , Xie Wanling , Tolaney Sara M. , Choueiri Toni K.
Published: June 2022

6520

Background: Real-world progression-free survival (rwPFS) and time to next line of therapy (TTNT) are two endpoints of clinical interest in patients with metastatic breast cancer (MBC). Their validation as intermediate endpoints for overall survival (OS), in a real-world setting, remains not fully established. Methods: We conducted a retrospective cohort study using the nationwide US Electronic Health Record-derived de-identified Flatiron Health database. The study population included pts diagnosed with MBC from Jan 1, 2011 to Feb 30, 2021. rwPFS was defined as the time from start of first-line systemic therapy for MBC to disease progression or death. TTNT was defined as the time from start of first-line systemic therapy until start of next line of therapy. The nonparametric Kendall tau correlation between each surrogate endpoint (rwPFS and TTNT) and OS was evaluated using the Hougaard copula model in the Weibull margin distribution. Kendall’s tau (τ) with its 95%CI was calculated across the entire dataset, and within each disease subgroup defined by receptor (ER and/or PR status defined as hormone receptor [HR], and HER2) status. This work was conducted on behalf of the imCORE network and the Dana-Farber Cancer Institute. Results: Overall, 9,770 patients with MBC were included. Median age was 63 years (IQR: 54-72 years). HR+/HER2- disease represented the most frequent MBC subtype (n=6,287; 64.4%), followed by HER2+ (n=2,096; 21.5%) and triple negative (n=1,387; 14.2%) disease. Median f/u was 41.5 months (95%CI: 40.4 to 42.8). Median OS in the overall population was 32.4 months (95%CI: 31.2 to 33.3). Median rwPFS was 11.5 months (95%CI: 11.1 to 11.9), and median TTNT was 11.1 months (95%CI: 10.7 to 11.5). Across the entire population, the correlation of rwPFS with OS was 0.54 (95%CI: 0.53-0.56), while the correlation of TTNT with OS was 0.47 (95%CI: 0.46-0.48) (Table). Conclusions: rwPFS and TTNT may represent meaningful intermediate endpoints for OS in patients with MBC overall, and within the different disease subgroups. [Table: see text]
Overall cancer survival inequalities in the state of São Paulo: A comparison between public and private systems.
Authors: Teixeira Bruno Casaes , Rider Alex , Holbrook Tim , Piercy James , Lux Michael Patrick
Published: June 2022

6525

Background: Brazilian cancer patients under the public healthcare system receive diagnoses and treatment at a later disease stage on average than private patients, likely due to the public system having less access than the private system to treatment and diagnostic technologies. The impact of the different healthcare systems on survival is unknown. We aimed to evaluate the difference in overall survival (OS) in cancer patients under public vs. private healthcare systems in São Paulo, Brazil. Methods: Data were drawn from the hospital-based cancer registry of the Fundação Oncocentro de São Paulo capturing clinical and demographic data including clinical setting (private/public), date of diagnosis, and disease stage. All patients had complete medical records and malignant, well classified tumors. Analyses used Cox proportional hazards regressions. For multivariate (MTV) and propensity score matched (PSM) analyses; tumor topology and morphology, patient demographics and diagnostic care setting were used as covariates. Analyses were performed for overall cancers and for 20 separate tumor types as recommended by the National Institute of Cancer. Results: Data from 189,850 patients were analyzed. For all cancers, the hazard ratio (HR) for OS for public vs. private healthcare was 2.30 (CI 95% 2.20 - 2.39) in univariate (UNV), 1.59 (CI 95% 1.52 - 1.66) in MTV and 1.69 (CI 95% 1.61 - 1.77) in PSM, indicating that patients under the public system were between 2.30 and 1.69 times less likely to survive their cancer (Table 1). The cancer type with the biggest HR using PSM was multiple myeloma (HR 2.37 CI95% 1.82 - 3.08). Conclusions: Our results show Brazilian cancer patients under the public healthcare system were in some cases more than twice as likely to die from cancer than private patients. Despite possible differences between these populations in lifestyle and other potential influencing factors, our results most likely reflect differences between the two systems in access to treatment and diagnostic technologies. Our findings highlight the inequality of care in public vs. private healthcare in Brazil. Focus should be on closing the gap between the two systems in cancer diagnosis and treatment.[Table: see text]
Bringing experimental therapeutics clinical trials network (ETCTN) to underrepresented population.
Authors: Baranda Joaquina Celebre , Doolittle Gary C. , Parikh Rahul Atul , Kasi Anup , Wulff-Burchfield Elizabeth Marie , Powers Benjamin , Pluenneke Robert E. , Hoffmann Marc Steven , Yacoub Abdulraheem , Saeed Anwaar , Corum Larry R. , Lin Tara L. , Sun Weijing , Mooney Margaret M. , Moscow Jeffrey , Doroshow James H. , Waters Brittany , Ivy S. Percy , Gore Steven , Jensen Roy A.
Published: June 2022

6542

Background: Access to health care including clinical trials (CT) leading to paradigm-changing cancer treatments are critical for high quality cancer care and equity in society. In this report, we highlight methods in accruing to ETCTN wherein underrepresented rural, low-income, and racial minorities comprise >50% of enrollment. Methods: University of Kansas Cancer Center (KUCC) is one of eight National Cancer Institute (NCI) designated cancer centers awarded CATCH-UP.2020 (CATCH-UP), a congressionally mandated P30 supplement to enhance access for minority/underserved populations to ETCTN precision medicine CT. KUCC catchment area is 23% rural by Rural Urban Continuum Codes (RUCC); almost 90 % of counties are designated primary care HPSA’s (Health Professional Shortage Areas). KUCC Early Phase and Masonic Cancer Alliance (rural outreach network) partnered to operationalize CATCH-UP. We engaged disease-focused champion investigators in disease working groups and MCA physicians who selected scientifically sound CT that fit catchment area needs. Patient and Investigator Voices Organizing Together, a patient research advocacy group provided practical feedback. MCA navigator coordinated recruitment. Telehealth was used for rural patients that would have a significant distance to travel just to be screened. Results: CATCH-UP was initiated in September 2020. Twenty-eight CT were activated, many in community sites. Average activation time was 81 days. Delays were mainly from CT amendments. KUCC enrolled the first patient in the CATCH-UP program. In 6 months, we met accrual requirements (24/year, 50% minorities). During first year, we enrolled 47 (>50% minorities), an increase of 680% from our average accrual of 6/year (>50% minorities) in ETCTN through Early Drug Development Opportunity Program (2016-2020). To date, we have enrolled 61, 54% from rural, HPSA, race and other minorities. Although the proportion of minorities did not change but remained high, this funding allowed us to substantially increase the number of patients from a catchment area with high proportion of geographically and socioeconomically underserved minorities given access to early phase CT through ETCTN. Conclusions: Amid COVID-19 pandemic, the NCI CATCH-UP program and methods we used allowed access to novel therapies for rural, medically underserved, and other minority groups. Funded by NIH: 3P30CA168524-09S2.
Impact of depression among adolescents and young adults with cancer.
Authors: Qiao Edmund Men , Qian Alexander , Mariano David J , Lee Terrence C. , Youngblood Eventine , Chou Linda , Murphy James Don
Published: June 2022

6549

Background: The incidence of adolescent and young adults (AYAs) with cancer continues to increase. The psychosocial burden of early cancer diagnosis within this unique AYA population remains poorly characterized. Without proper resources, these patients are likely to seek care in the acute care setting. For AYA patients, we evaluated the impact of malignancy on concurrent diagnosis with depression and on presenting to the emergency department (ED) with intentional self-injury. We further described the influence of concurrent depression diagnosis on hospital admission and extended length of stay (LOS) for AYA cancer patients. Methods: From the National Emergency Department Sample (NEDS), we identified patients between 15-39 years who presented to an ED in 2019. Diagnosis of cancer and depression were identified using International Classification of Diseases, 10th Revision coding. Separate multivariable logistic regressions evaluated the impact of cancer diagnosis on concurrent depression diagnosis and on presenting with intentional self-injury. For the subset of AYA cancer patients, multivariable logistic regressions evaluated the impact of depression on hospital admission and extended LOS ( > 14 days). Results: We identified 10,570,148 AYA patients, and 35,035 had cancer (0.33%). Among AYA cancer patients, average age was 31 and the cohort skewed White (48.7%), female (58.1%), and with Medicaid insurance (48.4%). The prevalence of depression among AYA cancer patients was 9.6% vs. 4.4% for patients without cancer. On multivariable regression, AYA cancer patients had a 46% increased odds of depression diagnosis (odds ratio (OR), 95% confidence interval (CI): 1.46. [1.43-1.49] P < 0.01) and 32% increased odds of intentional self-injury (OR, 95% CI: 1.32 [1.19-1.47] P < 0.01) when compared to patients without cancer. Additional significant factors associated with depression diagnosis among AYA cancer patients were White race, female gender, and Medicaid insurance. Within AYA cancer patients, a concurrent diagnosis with depression was associated with ̃3-fold increased odds of hospital admission (OR, 95% CI: 3.02 [2.90-3.14] P < 0.01) and a 31% increased odds of extended LOS (OR, 95% CI: 1.31 [1.23-1.39] P < 0.01). Conclusions: From this national sample, we found a significant association between cancer diagnosis and depression within AYA patients, with cancer diagnosis also increasing the risk of intentional self-injury. Furthermore, AYA cancer patients diagnosed with depression had increased risk of both hospital admission and extended LOS. Our results underscore the potential gap in psychological care for AYA cancer patients and highlight the need for stronger mental health resources for this at-risk population.
Racial disparities in diagnostic follow-up following BIRADS 0 mammogram.
Authors: Manik Ritika , Grady Connor B. , Ginzberg Sara , Edmonds Christine E. , Conant Emily F. , Hubbard Rebecca A. , Fayanju Oluwadamilola Motunrayo
Published: June 2022

6559

Background: Delays in follow-up after abnormal mammograms can lead to worse outcomes and may contribute to health disparities. BIRADS 0 mammograms necessitate additional diagnostic imaging, and BIRADS 4 or 5 mammograms should be followed by biopsy. The goal of this study was to investigate racial disparities in rates and timeliness of (1) diagnostic follow-up after a BIRADS 0 screening mammogram and (2) biopsy following a subsequent BIRADS 4 or 5 diagnostic mammogram. Methods: We included women ≥18 years old who underwent a screening mammogram at the Hospital of the University of Pennsylvania with an assessment of BIRADS 0 between September 2010 and February 2018. The distributions of time from screening to diagnostic mammogram and from BIRADS 4 or 5 diagnostic mammogram to biopsy were estimated using the Kaplan Meier method. Follow-up was censored at 365 days. Case-mix adjusted Cox proportional hazards models were used to estimate the association between race/ethnicity and time to diagnostic mammogram and biopsy. Results: We identified 6299 women (Asian/PI=257, Black=3223, Hispanic=124, White=2420, Other/Unknown=275) with 6880 BIRADS 0 screening mammograms during the study period. Following these BIRADS 0 mammograms, the overall rate of diagnostic mammograms within 365 days was 87.3% (n=6006 mammograms), with a rate of 90.6% (2432) for White women and 85.3% (2971) for Black women. For the 1151 BIRADS 4-5 diagnostic mammograms in the cohort, the overall rate of follow-up biopsies within 365 days was 91.8% (n=1057 biopsies), with a rate of 93.8% (396) for White women and 91.1% (575) for Black women. Compared to mammograms obtained by White women, those obtained by Black women were less likely to be followed up with a diagnostic mammogram (HR 0.71, 95% CI 0.63-0.80, p<0.001) and biopsy (HR 0.74, 95% CI 0.55-0.98, p=0.037) when indicated (Table). Almost 1/4 (24.2%, 95% CI 23.1-25.9%) of BIRADS 0 screening mammograms among Black women were not followed by diagnostic imaging within 30 days as compared to 14.6% among White women (95% CI 13.3-16.0%, p<0.001). 23.6% (95% CI 20.5-27.2%) of BIRADS 4-5 diagnostic mammograms among Black women were not followed up with biopsy within 30 days vs 18.7% for White women (95% CI 15.4-22.8%, p=0.61) (Table). These disparities persisted at 90 days. Conclusions: Racial disparities exist in rates of follow-up after BIRADS 0 mammograms. The additive effects of delays at each diagnostic step put Black women at disproportionately greater risk for worse outcomes. [Table: see text]
Disparity of treatment-related adverse events and outcome in patients with early-onset metastatic colorectal cancer (mCRC).
Authors: Meng Lingbin , Thapa Ram , Kim Richard D. , Laber Damian A. , Xie Hao
Published: June 2022

6560

Background: While the incidence of newly diagnosed early-onset mCRC has been increasing, disparity of treatment-related adverse events (AE) and outcomes of this patient population has been inadequately studied with inconclusive findings. We aimed to evaluate such age-related disparity and explore potential underlying causes. Methods: We used individual patient data from 3 clinical trials in Project Data Sphere where 756 and 467 patients with mCRC received first-line FOLFOX in study 1 (NCT 00305188, NCT00272051) and study 2 (NCT00364013), respectively. Clinical NGS data of 763 patients with mCRC from prospectively maintained Moffitt Clinical Genomics Database were used to assess genomic alterations. Patients were categorized into 3 age groups: <50, 50-65, and >65 years. Continuous and categorical variables were compared with t test and χ2 test, respectively. Kaplan-Meier method and log-rank test were used for survival analysis. Benjamini-Hochberg procedure was used to adjust for multiple comparisons. Results: Among 1986 patients included, 341 (17.2%) in the <50 group, 912 (45.9%) in the 50-65 group, 733 (36.9%) in the >65 group had similar baseline characteristics. Outcomes: Patients in the <50 group had shorter median OS compared to the 50-65 (15.5 vs 20.5 month, p=0.003) and >65 groups (15.5 vs 20.8 months, p=0.004) and shorter median PFS compared to the 50-65 (8.1 vs 9.4 month, p=0.039) and >65 groups (8.1 vs 8.6 months, p=0.07) in study 1. Findings were confirmed in study 2. Toxicity: Compared to other age groups, the <50 group had a higher incidence of severe (grade≥3) abdominal pain (8.4% vs 3.4%, p=0.01), severe anemia (6.1% vs 1.2%, p=0.001), nausea/vomiting (69.3% vs 58.8%, p=0.02), but lower incidence of severe diarrhea (6.1% vs 10.8%, p=0.02), severe neutropenia (25.7% vs 44.2%, p<0.001), and severe fatigue (4.5% vs 7.3%, p=0.02). The <50 group had earlier onset of nausea/vomiting (1.0 vs 2.3 weeks, p=0.01), mucositis (3.6 vs 5.4 weeks, p=0.05), and neutropenia (8.0 vs 9.0 weeks, p=0.04), and shorter duration of mucositis (0.6 vs 0.9 weeks, p=0.006). Outcomes + toxicity: In the <50 group, abdominal pain was associated with worse OS (HR 1.6, p=0.01). In contrast, fatigue (HR 0.66, p=0.03) and mucositis (HR 0.67, p=0.046) were associated with better OS. Neuropathy was associated with better PFS (HR 0.61, p=0.009). Genomics: Our NGS data showed that the <50 group had more ERBB2 amplification (10.5% vs 4.0%, p=0.04) and a trend of more TP53 mutations (80.2% vs 72.0%, p=0.07). These findings were confirmed in an independent mCRC cohort (n=471, MSK, Gastroenterology 2020). Conclusions: Patients with early-onset mCRC had worse outcome and unique treatment-related AE patterns. Distinct genomic profiles could explain some of the disparities. Our findings might improve a personalized management approach in patient selection for chemotherapy, counseling and AE monitoring.
Physician awareness of immune-related adverse events from checkpoint inhibitors.
Authors: Khalid Ahmed Bilal , Jalal Shadia Ibrahim , Durm Greg Andrew
Published: June 2022

6571

Background: Immune checkpoint inhibitors (ICIs) have been one of the most significant developments in Oncology over the last decade. Despite being very effective for certain patient subsets, they have a unique side effect profile different from conventional chemotherapy that can manifest as immune-related adverse events (IRAEs). With increasing ICI use, clinicians will increasingly encounter these adverse events and thus, adequate knowledge on recognition and management of IRAEs is very important. Methods: To assess physician knowledge on IRAEs of ICIs, an online survey was administered to resident physicians in internal medicine (IM), emergency medicine (EM) and family medicine (FM) as well as to faculty physicians in IM, and FM at 3 tertiary care hospitals in Indiana. Results: We sent the survey to 413 physicians out of which 155 responded with a response rate of 38%. Out of 155 physicians, 110 were residents and 45 were faculty (27 hospitalists and 17 primary care physicians). Pembrolizumab was identified as a checkpoint inhibitor correctly by 79% of physicians, nivolumab by 64% and ipilimumab by 55%. Twenty-five percent of physicians incorrectly believed infliximab and adalimumab were ICIs. Most physicians (93%) were able to identify the gastrointestinal tract as an IRAE site whereas only 57% and 67% were able to identify cardiovascular and renal systems as an IRAE site, respectively. Fifty-nine percent of physicians believed steroids negatively affect efficacy of ICIs and should be used with caution to treat IRAEs. Sixty-five percent of physicians incorrectly thought endocrinopathies due to IRAEs are usually reversible. Most physicians (79%) believed IRAEs most commonly manifest in the first 6 months of treatment. Forty-five percent of FM residents considered antibiotics as the mainstay of treatment in ICI associated immune mediated colitis; this was significantly different from EM (15%) and IM (8%) residents(p = 0.0004). When comparing between residency programs, on a scale of 0-100, IM residents felt significantly more comfortable identifying IRAEs secondary to ICIs (27.1±24.2) when compared to EM (12.2±12.7) and FM residents (9.4±13.8; p = 0.0009). There was no significant difference among IM (19.8±20.1), EM (11.9±13.6), and FM residents (11.6±18.9; p = 0.11) when comparing how comfortable they were in treating IRAEs. When asked what the best way would be to learn about IRAEs, 36% chose printed material and algorithms, 30% picked online teaching module and 30% chose one time in-person lecture from an Oncologist. Conclusions: Resident and faculty physicians in multiple specialties are not comfortable in the management and treatment of IRAEs due to ICIs. Given that most of these physicians are usually the first point of contact with patients, physician education on identification and treatment of IRAEs is needed. Early detection of these toxicities is critical for their resolution.
What is driving declines in oncology-prescribed opioids?
Authors: Townsend Tarlise , Cerda Magdalena , Chino Fumiko
Published: June 2022

6583

Background: Patients with cancer have experienced sharp declines in opioid prescribing during the past decade, raising concerns about insufficient pain management in a population with high rates of undertreated pain. It is unclear whether these declines are driven by certain oncology subspecialties, payors, or clinical guidelines regarding opioid prescribing released in/after March 2016. Methods: We conducted time series analyses using 2006-2019 IQVIA Longitudinal Prescription Data, which represents up to 92% of all U.S. prescription fills. Using log-linear regression stratified by group, we estimated annual percent change in opioid receipt by: subspecialty (medical oncology MO, radiation oncology RO, and surgical oncology SO); payor (third-party; Medicare, including Medicare Part D; Medicaid; cash/out-of-pocket); and pre- versus post-March 2016. Opioid receipt outcomes included: monthly fills of any opioid; monthly fills of extended-release/long-acting (ER/LA) opioids; and monthly number of patients receiving long-term opioid therapy (LTOT). Outcomes were per 1,000 survivors to account for temporal changes in cancer prevalence. Results: Between 2006 and 2019, 14,301,900 opioid fills were prescribed by oncologists to 3,476,354 distinct patients. Across all outcomes, MO had the highest levels of dispensing, followed by RO, then SO; for example, in 2006 MO dispensed 6.2 fills per 1,000 survivors (compared to 1.9 fills among RO, and 0.5 among SO). We observed substantial declines in all opioid outcomes. Per 1,000 survivors, there was an annual decline of: 5.7% (95CI: 5.1-6.3; total unadjusted decline 2006-2019=70.2%) in the rate of all opioid fills; 4.9% (95CI: 4.1-5.6; total unadjusted decline=66.8%) in ER/LA fills; 3.2% (95CI: 1.5-5.0; total unadjusted decline=56.2%) in LTOT fills, and 1.9% in average daily dose (95CI: 1.9-2.0; total unadjusted decline=29.8%). The annual decline in opioid fills prescribed by MO (7.1%, 95CI: 6.6-7.7) was sharper than for RO (5.9%, 95CI: 5.4-6.4) and SO (5.2%, 95CI: 4.7-5.7). Annual declines were steepest among fills paid out-of-pocket (14.5%, 95CI: 13.9-15.0), followed by those paid by Medicaid (13.1%, 95CI: 12.5-13.6), third-party payors (9.3%, 95CI: 8.7-9.9), and Medicare (2.4%, 95CI: 1.8-3.1). Declines in every outcome accelerated following clinical guidelines released in/after 2016. Conclusions: Opioids prescribed by oncologists declined dramatically across groups and outcomes. Medical oncologists were responsible for a disproportionate share of opioid fills in 2006, and for the sharpest declines. Out-of-pocket fills declined more sharply than fills covered by insurance and clinical guidelines may have contributed to accelerating declines. While de-escalation of opioid therapy may reduce risk of opioid-related harms to cancer survivors, care is needed to ensure cancer-related pain is appropriately treated.
Do publicly available OncoGenomic databases represent the population? A comparative analysis.
Authors: Brazel Danielle , Kumar Priyanka , Benjamin David Joseph , Moyers Justin Tyler
Published: June 2022

6588

Background: Large publicly available databases are important repositories for analyses of clinicogenomic research used for identifying clinically relevant biomarkers. Diversity among individuals in these repositories is key for ensuring applicability of findings to patient populations. Methods: We compared two publicly available pancancer databases from academic institutions: The Cancer Genome Atlas (TCGA) and United States (US) institutions from the American Association for Cancer Research (AACR) Project GENIE version 11.0 (APG) with cancer incidence statistics from The US Cancer Statistics (USCS) in 2018, the most recently available data. We compared demographic data from key individual cancer types (Lung, Colorectal, Prostate, Breast, Gliomas, and Leukemias) for gender, race, and ethnicity. Frequencies are displayed as percentages and compared by Chi-Squared method. Results: The USCS includes 1,708,921 new cases in 2018 while the TCGA includes 12,958 cases and APG includes 109,041 cases. Women account for 49.5% of all cancer diagnosis and similarly 50.4% of all cases in AACR and 51.2% of TCGA cases. Table summarizes key demographic differences. Amongst all cancer types, 78% of all US cancers occur in White patients however 84% and 83% of patients were White in AACR and TCGA respectively. 16% of prostate cancer cases occur in Black patients, but only 9% (n = 328/3993) of AACR and 11% (n = 51/484) of TCGA cases were Black (p < 0.01). However, while Black patients are only 2% of all breast cancer diagnoses, they accounted for 9% (n = 841/9871) of AACR and 16% (n = 203/1343) of TCGA cases p < 0.01). Patients of Hispanic ethnicity were underrepresented amongst the population and all single tumor types with Hispanics accounting for 8% of cases in USCS but only 5% in the AACR and TCGA (p < 0.01). Pancreatic and lung cancers, which have historically short survivals, both had lower median ages at sequencing compared to the median age of diagnosis. Median age of sequencing for pancreatic cancers was 65 in both TCGA and AACR, while median age at diagnosis in US is 70. Median age at diagnosis of lung cancers is 71 years in US, however median age was 67 in both AACR and TCGA. Conclusions: Patients with advanced age and minority races are underrepresented in publicly available American databases. To make informed analyses from genomic databases, the diversity of the population must be reflected in these databases and efforts must be made to increase representation of underrepresented groups. [Table: see text]