bluuebunny/crossref_metadata_2025 huggingface dataset:
Navigating disparities: Insights from a colorectal cancer screening program in federally qualified community healthcare centers.
Authors: Amin Robby , Turner Christopher , Santellano Brenda , Odhiambo Lorriane A. , Fleming Sable , Ibrahim Samah , Mitchell Katreena , Merchant Cynthia , Patten Douglas , Desai Koosh , Hotz James , Durham Lynn M. , Gabram Sheryl G. A. , Cortes Jorge E. , Islam KM Monirul
Published: June 2024

1537

Background: Colorectal cancer (CRC) is the second leading cause of cancer deaths in Georgia. Despite evidence for the effectiveness of CRC screening, disparities in access are prevalent in underserved populations. Georgia’s Federally Qualified Health Centers (FQHCs) struggle with low screening rates (42.8%), partly due to Georgia’s lack of Medicaid expansion, poor access to health services in rural areas, and deficiencies in coordinated strategies. The Georgia Colorectal Cancer Control Program (GCRCCP) was funded by the Centers for Disease Control and Prevention to implement evidence-based interventions (EBIs) in qualifying FQHCs across South Georgia. Here, we assess the program's impact on clinic-level screening rates (SR). Methods: Fourteen clinics with 12,159 CRC-eligible patients (ages 50-75) were enrolled from East Georgia Healthcare Center (EGHC) and Albany Area Primary Health Center (AAPHC). FQHC clinics had to have a SR below 60% to participate in the program. In addition to the EBIs (provider assessment and feedback, provider reminders, patient reminders, reducing structural barriers), the GCRCCP integrated provider education using the ECHO Model and navigation through a nationally recognized, evidence-based patient navigation program. We compared baseline (2020 and 2021) and follow-up data (2022) to determine the average change in SR over time, overall, and by demographic sub-groups. Results: The overall change in SR for the 14 clinics was +6.7%, from a baseline average of 45.3% to 52% in 2022. The average change in SR for EGHC clinics (n=9) was +11.5% (from 32.2 to 43.7%). Women had a higher SR (44.9%) than men (41.8%), but both realized an increase in SR, +10.5% and +9.1%. Non-Hispanic Black Americans (NHBA) experienced a higher increase in SR, +13.7% (from 37.2 to 50.9%) than their Non-Hispanic White (NHW) counterparts (+7.5% (from 29.8 to 37.3%)). The uninsured vs. insured followed a similar pattern (+15.3% (from 17.8 to 33.1%)) vs. +2.1 (from 45.9 to 48%). The average change in SR for AAPHC clinics (n=5) was +1.8% (from 58.4 to 60.2%). There was a decline in SR for men, -8.6% (from 64 to 55.4%), and an increase for women, +3.8% (from 58.2 to 62%). NHBA had a decrease in SR, -0.8% (from 61.2 to 61%), while NHW Americans had an increase in SR, +0.2% (from 53.8 to 54.2%). The uninsured and insured groups realized minimal increases of +0.6% (from 46 to 46.6%) and +0.8% (from 62 to 62.8%), respectively. Conclusions: The implementation of EBIs and patient navigation show varied potential to reduce disparities in accessing CRC screening in underserved populations. FQHC clinics that sustain implementation activities and workflow processes can benefit communities long-term and improve health equity.
Time to treatment initiation of lung cancer and contributing factors from 2015-2020 utilizing Surveillance, Epidemiology and End Results program database.
Authors: Di Vanna Mariela , Qaiser Saria , Shambhavi Shreya , Seeburun Sheilabi , MEDIK YUSRA B. , Iglesias Jose
Published: June 2024

1540

Background: Time from diagnosis of cancer to definitive therapy, or time to treatment initiation (TTI), has significant impact on prognosis. Kohorana et al performed an observational study in 2019 that found that TTI has increased in the United States with an absolute increased risk of mortality ranging from 1.2-3.2% per week in early-stage breast, lung, renal and pancreatic cancers. This study aims at identifying contributing factors and trends that can assist in shortening TTI of lung cancer. Methods: This is a retrospective cohort study conducted by review of Surveillance, Epidemiology and End Results Program database. Participants included 212,607 adults ages 18 and older diagnosed with lung cancer during 2015-2020. Variables contributing to TTI were studied like age, sex, race, marital status, geographic location, household income, stage and grade. TTI was measured as less than 30 days and greater than 30 days. ANOVA analysis was performed with SPSS and BlueSky Statistics, with p-value of <0.05 as significant. Results: TTI was 1.30 months in males and 1.31 months in females (p=0.038). In patients less than 65 years, TTI was 1.14 months, while those greater than 65 had a delay of 1.38 months (p<0.001). White patients had TTI of 1.26 months versus non-white patients, 1.44 months (p<0.001). Married patients had TTI of 1.24 months versus 1.44 months in widowed patients (P<0.001). Income less than $35,000 had less TTI (1.22 months) than income greater than $75,000 (1.33 months) (p<0.001), but the population earning <$35,000 was smaller (n=3,082) compared to >$75,000 (n=209,525), therefore not representative of the total population. Metropolitan had longer TTI than nonmetropolitan at 1.34 months versus 1.24 months, p<0.001. Grade IV had shorter TTI at 0.94 months with grades I and II having TTI of 1.42 and 1.46 months, respectively (p<0.001). Localized cancers had the longest TTI at 1.71 months versus distant at 1.01 months (p<0.001). More aggressive cancers had shorter TTI such as grade IV + distant at 0.76 months versus grade I + localized at 1.42 months. Association between grade and stage and impact on TTI was significant at p<0.001. Conclusions: This study revealed significant factors influencing the duration from cancer diagnosis to treatment among adult patients greater than 18 years old diagnosed with lung cancers. Shorter TTI intervals were observed for females, younger individuals (<65 years-old), white patients, married and those with higher tumor grades and distant cancer. Addressing these disparities requires targeted interventions that consider socioeconomic status, geographic location and cancer characteristics to ensure equitable access to timely and high-quality cancer care. Further investigation is warranted to fully understand the impact of factors such as household income and regional variations on treatment delays.
Symptoms reported by patients using an ePRO compared with those reported to nurses via telephone triage.
Authors: Kolodziej Michael A. , Ascha Mustafa S. , Frank Andrew , Hopper Chantel , Blau Sibel , Schaefer Eric S. , Telivala Bijoy , Kwiatkowsky Lavi
Published: June 2024

1542

Background: It is unclear how symptoms reported by an electronic patient-reported outcomes (ePRO) tool compare to symptoms reported to triage nurses by patient-initiated telephone calls. This work describes symptoms reported using each of these methods, and the percent of patients requiring an acute office visit triggered by these symptom reports. Methods: Among patients diagnosed with breast, lung, or colon cancer at three community oncology practices from 2020 to 2023, we examined ePRO symptom reports and compared these with symptoms reported via telephone triage to nurses by patients not using the ePRO tool. Results: 3,509 patients reported symptoms by ePROs, and 9,071 patients only reported by phone. Among patients reporting by ePRO, 2,162 submitted both ePROs and used telephone triage services. The most common symptoms that patients reported by ePRO reports (47,284 reports) were weakness / fatigue (72.9% of patients), pain (62.0%), nausea (39.2%), and headache (33.1%). The most common symptoms that patients reported by phone reports (19,344 reports) were pain (32.9%), weakness / fatigue (13.4%), swelling (11.1%), cough (10.3%), and diarrhea (9.4%). The median number of reports in the ePRO group was 6.0 (mean 13.5, IQR: 2.0, 15.0) per patient and the median number of reports in the phone triage group was 1.0 (mean 2.1, IQR: 1.0, 2.0) per patient. The most common high-urgency symptoms in the ePRO group (defined by practice defined symptom threshold) were weakness / fatigue (67.2% of patients), pain (55.7%), headache (40.2%), nausea (32.0%), and difficulty breathing (29.2%), while the most common high-urgency symptoms (as determined by the triage nurse) in the phone triage group were pain (32.4%), weakness / fatigue (11.8%), swelling (11.4%), fever/chills (10.1%), and cough (9.7%). More patients reported high-urgency symptoms by ePRO (n = 1,873, 53.4%) compared to those reported by phone triage (n = 2,448, 27.0%). Of patients in the ePRO group with a severe symptom who visited a site with acute care visits data, 330 patients (45.4%) had an acute care visit within 72 hours of a symptom report compared to 745 patients (47.5%) in the telephone triage group. Conclusions: Patients using ePROs reported more symptoms than patients reporting by phone, possibly because electronic reporting allows patients to easily communicate symptoms to care providers and receive prompt attention. Pain and weakness/fatigue were the most common urgent symptoms in both groups. The need for an acute care visit was the same in both groups. Further refinement of the ePRO tool including standardization of symptom thresholds, more uniform implementation in practices, and patient education with respect to optimal use of the ePRO may enable practices to replace telephone triage with ePROs.
Alliance A071401: Phase II trial of abemaciclib in patients with grade 2/3 meningiomas harboring somatic NF2 or CDK pathway alterations.
Authors: Brastianos Priscilla Kaliopi , Dooley Katharine , Geyer Susan Michelle , Gerstner Elizabeth R , Kaufmann Timothy J. , Iafrate A. John , Milhem Mohammed M. , Welch Mary Roberta , Kaley Thomas Joseph , Drappatz Jan , Chan Amy , Kumthekar Priya , Kamiya-Matsuoka Carlos , Strowd Roy E. , Cohen Adam Louis , Jaeckle Kurt A. , Robell Lindsay , Santagata Sandro , Barker Frederick G. , Galanis Evanthia
Published: June 2024

2001

Background: Systemic treatments are limited for patients with meningiomas that have progressed after surgery and/or radiation. Loss of NF2and CDKN2A/Bare common in higher grade meningiomas and promote meningioma progression in preclinical models. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance umbrella trial A071401, a genomically driven phase II study in recurrent or progressive meningiomas. Methods: Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily until progressive disease. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha =0.02). The threshold for promising results for PFS6 was 8+/24 pts. For RR, 24 evaluable pts provided >89% power to detect RR >20% (vs. null 2.5%; alpha = 0.021). The threshold for promising results for RR was 3+/24 pts. Results: Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received treatment. The mean number of treatment cycles administered was 7 and median follow-up since start of treatment was 11 months. The first 24 pts that met eligibility criteria and began treatment were considered evaluable for the primary endpoint analysis. Of the 24 pts evaluated, 58% were female and the median age was 62 years. The observed PFS6 rate was 54% (13/24 pts, 95% confidence interval 33-75%), thus the study met PFS6 endpoint. No objective responses were observed. Of the 36 pts who started treatment, eight had a grade 3 and two had a grade 4 adverse event at least possibly related to treatment. Grade 3 toxicities included anemia (2), neutropenia (2), leukopenia (1), blurry vision (1), diarrhea (2), fatigue (2), ALT elevation (1), dehydration (1), hyperkalemia (1), hyponatremia (1), dizziness (1), acute kidney injury (1), and thromboembolic event (1). Grade 4 toxicities included ALT elevation (1), AST elevation (1) and vomiting (1). Conclusions: Abemaciclib was well tolerated and resulted in an improved PFS6. The overall trial endpoint was met. Abemaciclib warrants further investigation for the treatment of patients with progressive grade 2/3 meningiomas. Support: U10CA180821, U10CA180882; UG1CA189867 (NRG Oncology); Eli Lilly; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02523014 .
Effect of breast cancer receptor subtypes and CSF cytology status on survival for patients with leptomeningeal disease.
Authors: Niraula Sujan , Gouli Sugam , Baran Andrea M. , Tyburski Haley , Zhang Huina , O'Regan Ruth , Mohile Nimish , Anders Carey K. , Hardy Sara , Dhakal Ajay
Published: June 2024

2025

Background: Leptomeningeal disease (LMD) in metastatic breast cancer (MBC) carries a poor prognosis. Data on the effect of BC sub types and CSF cytology results on overall survival (OS) are lacking. This single institution retrospective study compares OS among MBC with LMD across BC sub types and CSF cytology results. Methods: This study included patients (pts) diagnosed with MBC LMD from Jan 2010 to Jan 2023. BC sub types were defined as (1) ER positive (+)/HER2 negative (-), HER2+, triple-negative BC (TNBC), (2) HER2 0 [immunohistochemistry (IHC) score 0], HER 2 low [ IHC 2+ with fluorescence in-situ hybridization negative OR IHC 1+], HER2+. ER and HER2 positivity were defined per ASCO/CAP criteria. CSF cytology sub types were CSF+ (for malignant cells), CSF-, and CSF not tested. Baseline characteristics were compared using Fisher’s Exact and Wilcoxon rank-sum tests. OS among sub types was evaluated using Kaplan-Meier analysis and compared using log rank test. For multivariate analysis, a step wise model selection was performed after inclusion of sub type of interest; and variables meeting entry (p<0.10) and staying criteria (p<0.05) were included in final Cox model. Results: Out of 219 patients screened, 69 pts were registered. Median OS and associated 95% confidence interval (CI) within BC sub types in analyses 1 and 2 and CSF sub type analysis are shown in the table. OS in analysis 1 was not significantly different by BC sub types. In multivariate analysis, TNBC sub type had significantly shorter OS than ER+/HER2- group [Hazard Ratio (HR) 2.64, 95% CI (1.23, 5.80) (p=0.04)] after adjusting for interval from MBC to LMD diagnosis and CSF cytology status. OS by BC sub types in analysis 2 was not significantly different in unadjusted and multivariate analyses. CSF- group had significantly better OS compared to CSF+ or CSF not tested group in unadjusted analysis (Table) and multivariate analysis [CSF+ vs CSF- HR 4.5 95% CI (1.75-12.11); CSF not tested vs CSF- HR 2.91 95% CI (1.45-6.26), overall p=0.002]. Conclusions: This single institution study on MBC pts with LMD showed that BC receptor sub types were significantly associated with OS when adjusted for the interval from MBC to LMD diagnosis and CSF cytology group. This study showed significantly improved OS among patients with negative CSF cytology compared to those with positive cytology or those not tested, indicating a novel prognostic value of CSF cytology (currently on diagnostic value) for MBC LMD. These findings will be further validated. [Table: see text]
A randomized, controlled, phase 2 trial of nivolumab plus standard-dose or low-dose bevacizumab for recurrent glioblastoma (NAVAL).
Authors: Ahluwalia Manmeet Singh , Peereboom David M. , Ozair Ahmad , Khosla Atulya Aman , Rauf Yasmeen , Nayak Lakshmi , Ciolfi Marci , Alban Tyler , Grabowski Matthew , Rayman Pat , Diaz Marcella , Lathia Justin , Lee Eudocia Quant , Wen Patrick Y. , Reardon David A.
Published: June 2024

2072

Background: PD-1/PD-L1 inhibition has demonstrated limited efficacy for recurrent glioblastoma (rGBM) across prior RCTs. VEGF, a proangiogenic factor upregulated in rGBM, contributes to tumor-associated immunosuppression. Preclinical and observational clinical data indicate a potential dose-dependent effect of anti-VEGF therapy on immune response. This RCT evaluated anti-PD-1 plus anti-VEGF therapy for rGBM. Methods: NAVAL was a multicenter, open label, phase 2 RCT that enrolled 90 patients (≥18 years) with GBM at first recurrence. Participants received nivolumab (240 mg IV Q2 weeks), and were 1:1 randomized to concurrent 10 mg/kg bevacizumab ( standard-dose arm) or 3 mg/kg bevacizumab ( low-dose arm) administered IV biweekly. Stratification factors included age, performance status, extent of resection, and MGMT methylation status. Primary endpoint was overall survival (OS) at 12 months (OS-12). Other outcomes were overall objective response rate (ORR), median progression-free survival (PFS), PFS at 6 months (PFS-6), and safety. Exploratory genomic and immune profiling using CITEseq was performed in 16 patients. Results: 90 patients were enrolled with median age of 60.6 years (range 27-86). 35 patients were MGMT methylated, 53 were unmethylated and 2 were indeterminate. Final analysis had 87 evaluable patients, with median follow-up of 146 days (range 7-1239). There were 3 complete responses (3.4%), 29 partial responses (33.3%), 37 stable disease (42.5%), and 18 progressive disease (20.7%). OS-12 was 41.1% and 37.7% in standard-dose and low-dose arms respectively, with PFS and ORR data in table. Post-hoc analysis demonstrated survival benefit for patients aged ≥60 years in standard-dose arm. Most frequent toxicities (>20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Grade 3-4 toxicities included hypertension (7.8%), fatigue (5.6) and non-neurological toxicities. Differential changes across trial arms were seen in myeloid-derived suppressor cells (MDSCs) post-therapy. Network medicine identified VEGF as target to reduce MDSCs. VEGF was found expressed by MDSCs of mainly responder patients. Differential gene expression analysis identified increased pro-inflammatory gene signatures in standard-dose arm. Conclusions: Overall PFS and OS were similar for nivolumab plus standard- or low-dose bevacizumab for rGBM, with post-hoc survival benefit seen in standard-dose arm in elderly. Standard-dose bevacizumab was associated with increased systemic inflammatory response and reduced immunosuppressive MDSCs. Clinical trial information: NCT03452579 . [Table: see text]
Gender disparity in chimeric antigen receptor T-cell therapy utilization and outcomes in the United States.
Authors: Solipuram Divya , Mehta Kathan , Siddappa Malleshappa Sudeep Kumar
Published: June 2024

2556

Background: Chimeric antigen receptor T-cell [CART] therapy has marked a new era in the treatment of relapsed/refractory hematological malignancies since its approval in 2017. Racial disparity was studies previously but not gender. Current study aimed to evaluate gender disparity in CART therapy utilization and outcomes. Methods: This cross sectional study was done using National Inpatient Sample [NIS], the largest database available in the US. Inpatient admissions of adults who received CART therapy for various indications during year 2020 were included. Results: A total of 6915 patients were admitted to hospital for CART therapy in 2020 with an overall inpatient mortality rate of 1%. Mean age of the patients was 57yr. Majority were White [64%], with a higher median household income, admitted to urban and large sized hospitals and predominantly covered by Medicare or private insurance [~80%]. Study population was divided into males and females and outcomes were compared. Females were significantly younger with lower Charlson comorbidity index and higher utilization of CART therapy [81% vs 19%] compared to males. Females had 86% lesser odds of mortality compared to males (Odds Ratio [OR] 0.14; 95% confidence interval [CI] 0.04-0.47; p value 0.001). Females had significantly lesser hospitalization charges [mean decrease $471,193; p value 0.000] and length of stay [mean decrease 8 days; p value 0.000] compared to males after adjusting for confounders. Racial differences in outcome were compared after multiple imputation was used to correct for 4% missing data in the race category in NIS 2020. There was no statistically significant difference in mortality, length of stay or hospitalization charges between Whites, Blacks and Hispanic races similar to previous studies. Conclusions: Eligibility criteria for CART therapy includes patients with good performance status and organ function with less comorbidities. Our study found that females were younger, healthier and therefore qualified better for CART therapy compared to males. Hence they had significantly higher utilization of CART therapy. In addition, among the population receiving CART therapy, females had better outcomes compared to males in terms of mortality, length of stay and hospitalization charges. In general, males have higher incidence and mortality with poorer outcomes in most hematological malignancies where CART therapy is a treatment option. Measures at modifying and improvising CART therapy to cater to more male subjects will not only reduce gender disparity but also improve overall survival and reduce disease burden. [Table: see text]
A plasma-based proteomic platform for predicting clinical benefit from immune checkpoint inhibitors in multiple cancers.
Authors: Sela Itamar , Lahav Coren , Lowenthal Gil , Harel Michal , Elon Yehonatan , Yellin Ben , Dicker Adam P. , Halaban Ruth , Marte Jenn , Sznol Mario , Gulley James L.
Published: June 2024

2568

Background: Immune checkpoint inhibitor (ICI)-based therapies are preferred treatment options for multiple cancer types. However, there is an unmet need for predictive tests that can identify patients likely to benefit. PROphet-NSCLC is a commercially available pretreatment plasma proteomic test that predicts clinical benefit from first-line PD-(L)1 inhibitor-based therapy in patients with metastatic non-small cell lung cancer (NSCLC), guiding the choice between ICI monotherapy versus ICI-chemotherapy. Here, we evaluate the broader clinical utility of PROphet-NSCLC by testing its predictive capabilities across diverse cancer types. Methods: Pre-treatment plasma samples and clinical data were collected for an observational study from patients with metastatic melanoma (n=68) and HPV-related cancers (n=43; NCT03427411) treated with PD-(L)1 inhibitor-based therapies. HPV-related cancers included anogenital squamous cell carcinoma (n=16), cervical carcinoma (n=18), and head and neck squamous cell carcinoma (n=9). Patients were assigned a PROphet-positive or -negative result based on computational analysis of SomaScan-derived proteomic profiles in pre-treatment plasma samples. Overall survival (OS) and progression-free survival (PFS) in PROphet-positive- and -negative groups was analyzed with the Kaplan-Meier method. Hazard ratios (HR) were calculated from univariate and multivariate Cox proportional hazard models. Results: In the melanoma cohort, PROphet-positive patients (n=51) displayed a significant OS benefit in comparison to PROphet-negative patients (n=17; median OS 92.8 months vs. 9.5 months, HR=0.14, 95% CI: 0.06-0.34, p<0.0001), consistent with the clinically validated predictive performance of the test in patients with NSCLC. OS results remained significant after correcting for sex, age, histology, ECOG performance status, and treatment type (HR=0.05, 95% CI: 0.01-0.25, p<0.001). In PROphet-positive patients, PD-1+CTLA-4 inhibitor combination therapy (n=27) was superior to PD-1 inhibitor monotherapy (n=24; OS: median 118.4 vs. 48.3 months, HR=0.58, p=0.24; PFS: median not reached vs. 10.8 months, HR=0.48, p=0.04). PROphet-negative patients displayed similarly poor outcomes with either treatment, providing a rationale to consider alternative therapies for such patients. In the HPV-related cohort, the median OS in PROphet-positive (n=10) vs PROphet-negative (n=33) groups was 43.6 vs 4.4 months (HR=0.22, 95% CI: 0.08-0.59, p=0.001), with similar trends per sub-cohort. Conclusions: Our findings show that the PROphet-NSCLC test can be applied to PD-(L)1 inhibitor-treated melanoma and HPV-related cancers, suggesting applicability to cancers beyond NSCLC. Analysis of additional patient samples is needed to explore the potential utility of PROphet-NSCLC for informing treatment decisions for a broad range of cancer types.
Updated results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with EC-naïve metastatic BRAF V600E colorectal cancer (CRC) in the phase 1b/2 HERKULES-3 study.
Authors: Parikh Aparna Raj , Chiorean E. Gabriela , Atreya Chloe Evelyn , Zheng Lei , Kopetz Scott , Spira Alexander I. , Spigel David R. , Cui Yue , Osgood Ryan , Tran Rebecca , Morris Shannon R. , Ulahannan Susanna Varkey
Published: June 2024

3517

Background: The RAS/MAPK pathway (including BRAF) is dysregulated in a broad range of cancers including CRC, resulting in downstream activation of ERK1/2. Patients (pts) with metastatic CRC with BRAF V600E mutation (BRAF V600E mCRC) have dramatically poorer survival rates than those with non-BRAF V600E mutated CRC, highlighting the need for novel therapies. The combination of a BRAF plus EGFR inhibitor is approved for the treatment of pts with BRAF V600E mCRC; however, objective response occurs in only 20% of pts. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK. ERAS-007 alone or in combination with encorafenib and cetuximab (EC) showed promising in vitro and in vivo activity in BRAF V600E CRC models, supporting investigation of the potential clinical benefit of ERAS-007 + EC in pts with BRAF V600E mCRC. Methods: HERKULES-3 is a Phase 1b/2 study to assess the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety, tolerability, PK, and preliminary clinical activity of the combination of ERAS-007 + EC in pts with EC-naïve BRAF V600E CRC. Results: As of 30 November 2023, 19 (EC-naïve and EC-pretreated) pts have been dosed with ERAS-007 100 mg twice daily-once a week (BID-QW) in combination with EC (300 mg oral daily + 500 mg/m2 intravenous infusion every 2 weeks). The treatment-emergent AEs (TEAEs) occurring in ≥25% of pts were dermatitis acneiform (52.6%); nausea and fatigue (47.4% each); diarrhea (42.1%); constipation, headache, and hematuria (31.6% each); and vomiting, anemia, and infusion-related reaction (26.3% each). There were no Grade 4 TEAEs. One pt suffered a Grade 5 unrelated event of respiratory failure. There were no Grade 3 treatment-related AEs that occurred in more than 1 pt. There were no ERAS-007-related AEs that led to discontinuation of ERAS-007. Of the 19 pts, 11 were EC naïve and 10 of 11 were efficacy evaluable. In the EC naïve efficacy evaluable pts, the ORR was 40% with 3 of the 4 responses confirmed. The maximum duration of response is > 15 months; updated data will be presented. Conclusions: ERAS-007 100 mg BID-QW in combination with EC was safe and well tolerated with preliminary evidence of promising clinical activity. These results support continued evaluation of this combination in EC naïve pts with BRAF V600E CRC. Clinical trial information: NCT05039177 .
PREVECOL, a predictive model for early detection of colorectal cancer and precancerous lesions in liquid biopsy.
Authors: Planelles Lourdes , Guler Ipek , Jiménez-Martínez Marta , Babiker Rashid , Castillo Lourdes , Monsalve Carmen , Sanchez-Viñes Elena , Arroyo Rocío
Published: June 2024

3629

Background: Colorectal cancer (CRC) is the second cause of cancer-related deaths worldwide. Most of these deaths could have been prevented by increasing the effectiveness of CRC screening programs, which exhibit a low participation rate, partly due to the limited available screening options, alongside discomfort associated with the screening procedure (faecal test). Liquid biopsy-based technology offers new alternatives to improve CRC early detection. CRC and advanced adenoma (AA) patients show molecular alterations at different biological levels that can be detected in peripheral blood and used for diagnostic purposes. AMADIX has developed PreveCol, an innovative blood test based on molecular biomarkers and clinical features for early detection of CRC and AA, before the onset of the first symptoms. We present the validation of PreveCol predictive model through a European prospective clinical study involving average-risk population actively engaged in a real CRC screening program. PreveCol has been granted with the Breakthrough Device Designation by the FDA in December 2023. Methods: Samples from two prospective clinical studies were used for training and validation. A case-control study (n= 538 individuals: 173 CRC, 181 AA, 184 Controls; 13 Spanish sites) and a clinical study based on a real CRC screening program (n= 3163 individuals: 78 CRC, 156 AA, 146 HRPL, and 2783 Controls; 9 European sites). PreveCol molecular signature (11 proteins and 10 miRNAs), was determined in plasma samples using RT-qPCR and ELISA/CLIA. Machine learning techniques were used to develop an ensemble algorithm. K-fold cross validation techniques were used in the training to set the hyperparameters for each model. Hyperparameter optimalization was performed to find the best parameters of the grid. Once the algorithm was locked and the clinical cut-off was established in the training set, the signature was validated in the European prospective study sub-cohort. Results: For CRC detection, PreveCol demonstrates an Area Under the ROC curve (AUC) of 92%, with a sensitivity (SS) of 81.8% and specificity (SP) of 86%. Moreover, the model exhibits high sensitivity (above 90%) in identifying CRC in early stages (stages 1 and 2), as well as lesions located in the proximal colon. In addition, the AUC of PreveCol for Advanced Adenomas detection is 86.88%, (SS of 70.8% and SP of 86%), showing that PreveCol presents higher sensitivity compared to other identified tests for detecting precancerous lesions. Conclusions: These findings highlight PreveCol's potential to significantly impact on patient prognosis and survival by facilitating the early detection of CRC and premalignant lesions as well as lesions in critical areas of the colon, thereby contributing to improved screening efficacy and patient outcomes.
Association of plasma kynurenine (KYN) with plasma osteopontin (OPN) in patients with locally invasive breast cancer.
Authors: Ephraim Adam , Leatheng Chanbormey , Lu Ziyao Eric , Xia Xiaoqing , Pirruccello Jonathan P. , Marotti Jonathan D , MacKenzie Todd , Chamberlin Mary D.
Published: June 2024

e12551

Background: OPN is a matricellular protein implicated in several aggressive malignancies as both a prognostic marker and mechanistic driver of tumor development and metastasis, but little is known about what drives its increased expression in these settings. KYN, the biochemically active metabolite of tryptophan metabolism, is known to be involved in cancer immune evasion, cancer cell proliferation, chromosomal instability, angiogenesis, metastatic dissemination, and chemoresistance. In this study, we demonstrate that OPN levels are significantly elevated in plasma of patients requiring breast surgery for suspicious masses and is directly correlated with KYN plasma levels, which were also elevated in this population. Methods: We prospectively collected peripheral blood samples of 60 patients who required routine breast surgery for either benign or malignant masses. Plasma was obtained by centrifugation from the collected blood samples that were stored at -80℃. Samples were collected prior to any treatments or surgeries. This study is IRB approved, and participants provided written informed consent. High-performance liquid chromatography (HPLC) tandem mass spectrometry was carried out by the Dartmouth Clinical Pharmacology Shared Resource. Logistic regression was used to assess relationships among variables in the study population using the R language. Results: There is strong evidence to suggest that plasma KYN is directly related to OPN plasma levels in this group of 60 patients’ plasma samples with a correlation coefficient of 0.296 (p=0.024), 95% CI [0.0414-0.515]. Based on the p-value and confidence interval, there is statistical evidence to suggest a positive significant linear relationship between plasma KYN and OPN levels. Increased age and BMI, menopausal status, KYN’s substrate Tryptophan (TRP), and TNFα correlated neither with OPN levels nor event free survival (as defined by disease progression, complications including fractures, development of metabolic disease, or occurrence of secondary malignancy). Conclusions: Our data demonstrates a statistically significant linear relationship between KYN and OPN in plasma samples of patients undergoing breast surgery for suspicious lesions—offering new mechanistic insights into OPN—a biomarker implicated in cancer metastasis across several different cancer types. This data suggests that KYN, which is a known agonist of several harmful cancer-driving pathways, is directly related to OPN concentration in plasma of patients with early breast cancer. Further research investigating systemic concentrations of OPN in plasma is essential for gaining a comprehensive understanding of its mechanisms in tumor metastasis, as well as for exploring targeted therapeutic strategies to mitigate its detrimental effects.
Clinical features of breast cancer in Ashkenazi Jewish carriers of the two founder BRCA1 pathogenic variants.
Authors: Michaelson-Cohen Rachel , Lenz Lee Sarah , Kadouri Luna , Yablonski-Peretz Tamar , Levy-Lahad Ephrat , Paluch-Shimon Shani
Published: June 2024

e12557

Background: Germline pathogenic variants (PVs) in BRCA1 and BRCA2 are the most common cause of hereditary breast and ovarian cancer. Carriers have a significantly elevated risk of developing breast cancer (BC) and ovarian cancer (OC) compared to the general female population. Two prevalent PVs in Ashkenazi Jews (AJ) in the BRCA1 gene are 185delAG and 5382insC. This study aims to compare clinical features of disease between the PV carrier groups. Methods: Data was collected retrospectively on 282 BC patients who were carriers of 5382insC or 185delAG, treated in Hadassah and Shaare Zedek Medical Centers between the years 1978 and 2021. Data collected included features such as age at disease onset, staging at diagnosis, additional malignancies or recurrence of disease, pathological features such as hormone receptor status and HER2 status (tumor subtype), and treatments. Disease characteristics and outcomes were compared. Results: There were 207 carriers of the 185delAG PV, while 75 carried the 5382insC PV. Amongst carriers of 185delAG, vs. 5382InsC, 58.1% vs. 35.8% (p<0.01) had triple negative BC (TNBC), while 28.2% vs. 52.6% (p<0.01) had hormone positive BC, respectively (Table). There was no significant difference in disease-free or overall survival, even after adjusting for age, stage and other potential confounders. Although it appeared that 5382insC carriers suffered a higher rate of OC (14% vs. 9.6%), and that 185delAG had a higher rate of non-OC malignancies (8.2% vs. 4%), these differences did not reach statistical significance. Conclusions: Our study suggests that 5382insC and 185delAG differ in their patterns of disease. Despite the lower rates of TNBC, 5382insC carriers had similar survival to 185delAG carriers. This could suggest that the hormone receptor positive disease amongst 5382InsC carriers had a less favorable course of disease, with a similar outcome as in those with TNBC. Further studies are warranted to better understand this pattern of disease aggression. [Table: see text]
Short-term and long-term survival outcomes in patients with invasive lobular carcinoma vs. invasive ductal carcinoma of the breast.
Authors: Lin Shuwen , Anampa Mesias Jesus Del Santo
Published: June 2024

e12564

Background: Invasive lobular carcinoma (ILC) accounts for 10% of all invasive breast cancer and has distinct histological and biological features compared to the most common breast cancer histological subtype, invasive ductal carcinoma (IDC). ILC is more endocrine sensitive and chemotherapy resistant than IDC and has a different metastatic pattern. There is lack of conclusive data on the differences in survival outcomes between ILC and IDC. We aimed to assess the short-term and long-term survival outcomes in patients with ILC and IDC in a large population database. Methods: This is a retrospective, population-based study using data from the Surveillance, Epidemiology, and End Results database. We included women > 18 years with stage I-III ILC or IDC diagnosed from 1992-2020. Multivariable logistic regression was used to assess factors associated with different treatment modalities in patients with IDC vs. ILC. We estimated breast cancer-specific survival (BCSS) using Kaplan-Meier methods and their survival rates were compared using the log-rank test. We analyzed BCSS at different time points using a cox regression model with time-varying coefficients. Results: 343,397 patients with IDC and 39,859 patients with ILC were included in this study. Patients with ILC were older (63.0 ± 12.5 years vs. 59.2 ± 13.5 years, p<0.001). There were more non-Hispanic white patients with ILC vs. IDC (76% vs. 67%, p<0.001). Patients with ILC had more advanced disease: more stage III disease (16% vs. 11%, p<0.001), more T3-T4 disease (15% vs. 6%, p<0.001), and more N2-N3 disease (12% vs. 9%, p<0.001). Patients with ILC also had a higher frequency of hormone receptor positive disease (97% vs. 81%, p<0.001). Fewer patients with ILC had grade 3-4 tumors (9% vs. 36%, p<0.001). Our multivariate analysis showed that compared to patients with IDC, patients with ILC were more likely to undergo mastectomy (OR=1.85, p < 0.001) and radiation (OR=1.20, p<0.001), but less likely to receive chemotherapy (OR= 0.92, p<0.001). After adjusting for clinicopathological features, treatment modalities, and socioeconomic variables; compared to patients with IDC, patients with ILC had better BCSS in the first five years (HR=0.71, p <0.001), but worse BCSS in later years (HR=1.30, p<0.001 in year 6-10; HR=1.75, p<0.001 in year 11-15; HR=2.17, p<0.001 in year 16-20). Annual hazard models show that IDC peaked at recurrence in the first 5 years after diagnoses, and the hazard rate declines gradually after that. ILC peaked at recurrence in the first 5 years after diagnosis with minimal decrease in hazard rates after that. Conclusions: BCSS of patients with ILC is better in early years but worse in later years compared to patients with IDC. Future studies are needed to identify predictors of late relapses in ILC, and novel therapeutic strategies are required for these patients.
Evaluation of the immune landscape associated with the efficacy of immunotherapy in patients with triple-negative breast cancer: Starlet study, synergy between research and clinical work.
Authors: Gasparini Elisa , Ragazzi Moira , Manzotti Gloria , Torricelli Federica , Salviato Elisa , Bisagni Alessandra , Zanetti Eleonora , Pappalardo Annamaria , Coiro Saverio , Ferrari Guglielmo , Soncini Silvia , Bisagni Giancarlo , Pinto Carmine , Ciarrocchi Alessia , Reggiani Francesca
Published: June 2024

e12568

Background: Neoadjuvant chemotherapy (NACT) is the standard treatment for early-stage TNBC and achieving a pathological complete response (pCR) is an essential prognostic factor. Recently, by applying a morphology-guided spatial transcriptomic approach, we showed that intratumoral infiltrating lymphocytes (iTILs) and stromal Natural Killer (NK) cells are major determinants of chemotherapy efficacy in TNBC. These data underline how spatiality and molecular activation of immune cells are essential to enhance the efficacy of the NACT in TNBC. The fact that immune cells are important players in this setting is corroborated by the clinical success showed by the KEYNOTE-522 study (Schmid et al, NEJM 2020). This trial paved the way for the use of immunotherapy in TNBC, obtaining a significant improvement in the patient’s overall response. The implementation of chemotherapy with immunotherapy in the TNBC neoadjuvant treatment implicates several compelling questions, including how to further increase the percentage of pCR overcoming resistance mechanisms and how to improve the personalization of treatment, evaluating which patients can benefit from a therapy de-scalation or another combined therapeutic strategy. Methods: we enrolled 43 patients with early-TNBC treated with the KEYNOTE-522 regimen. To further clarify the immune dynamics that lead to a complete response to pembrolizumab in these patients, we collected peripheral blood before and after neoadjuvant treatment to isolate peripheral blood mononucleated cells (PBMCs). We applied asingle-cell transcriptome analysis to shape any variations in circulating immune cells occurring during neoadjuvant treatment and associated with patient response. In addition, we collected residual tumor at surgery from partial responders and derived three-dimensional organoids that recapitulate the characteristics of patient tumor. Results: Immune profiling of PBMCs indicated that patients showing pCR during NACT and immunotherapy displayed a decrease of B Lymphocytes and a concomitant enhancement of Natural Killers. We successfully established TNBC patient-derived organoids from 8 TNBC patients. Conclusions: our ongoing study is defining the immune-related molecular mechanisms driving pembrolizumab and chemotherapy response in the neoadjuvant treatment of TNBC patients. Our findings can improve our understanding of which immune populations are determinant players in anti-TNBC immune response and can be proposed as novel biomarkers of pembrolizumab efficacy during the neoadjuvant treatment.
Spatial transcriptomic and proteomic insight into Trop-2, HER2, and AR expression: A pathway to tailored therapies in triple-negative breast cancer.
Authors: Carausu Marcela , Lifrange Frédéric , Venet David , Rouas Ghizlane , Wang XiaoXiao , Larsimont Denis , Rothé Françoise , Sotiriou Christos
Published: June 2024

e12576

Background: Triple-negative breast cancer’s (TNBC) dismal prognosis demands more effective therapy selection. Previously described molecular subtypes reveal its heterogeneity but lack spatial insight and are not currently used in clinical practice. Here, we aim to evaluate by immunohistochemistry (IHC) the expression of key biomarkers in TNBC and its correlation with spatial gene expression obtained by spatial transcriptomics (ST). Methods: We studied a retrospective cohort of 92 patients (pts) treated at the Institut Jules Bordet in Belgium with primary surgery for early TNBC. ST (Visium Spatial Gene Expression, 10X Genomics) was previously performed on fresh frozen surgical samples. Using serial sections of these samples, we performed duplex IHC staining for Trop-2/androgen receptor (AR) and HER2/Ki-67. IHC staining was scored using H-score (Trop-2), Allred score (AR), and current guidelines (Ki67/HER2), adding the ultra-low and null HER2 categories. Statistical analyses included descriptive statistics, Spearman correlation, Mann-Whitney test, and Kaplan-Meier with log-rank tests for estimating outcome distribution. Results: Of 92 pts included, 4 (4.3%), 25 (27.2%), 28 (30.4%), and 35 (38%) pts had HER2 2+, 1+, ultra-low, and null, respectively, tumors. Importantly, we observed a significant difference in tumor cell-derived ERBB2 gene expression of HER2 ultra-low versus HER2 null tumors ( p<0.0001), while there was no difference in ERBB2 expression between HER2 ultra-low and HER2 1+ tumors ( p=0.49). HER2 expression was not correlated with prognosis. Trop-2 expression by IHC was high, medium, and low in 67%, 23%, and 10% of pts, respectively. IHC expression correlated well with tumor-derived gene expression (r=0.54), with intrasample heterogeneity observed both in IHC and spatial gene expression. Trop-2 expression was prognostic, pts with high Trop-2 H-score tumors having significantly worse outcome ( p=0.021). In this cohort, 25%, 40.2%, and 34.8% of pts had AR Allred scores of 0-2, 3-5, and 6-8, respectively. Tumor AR gene expression was well correlated with IHC AR expression (67.7%). IHC AR expression was associated with the presence of adipose tissue in the stroma (r=0.23, p=0.025) but not with prognosis. Of note, we report for the first time, to our knowledge, for TNBC, AR expression both in tumor and stroma cells, both at the IHC and gene expression levels. Importantly, we could construct a classifier that identifies luminal androgen receptor tumors, using AR Allred score > 5 and Ki67 ≤ 40%, with a PPV of 93% and an NPV of 96%. Conclusions: ST data has the potential to improve easily accessible IHC classifiers, with the aim of refining patient selection for ADC and anti-AR therapies in TNBC.
Uncovering of NRAGE/JNK and PI3K/AKT pathways through serial WGS of patients with breast cancer.
Authors: Lee In Hee , Lee Soo Jung , Lee Yunji , Kang Byeongju , Lee Jeeyeon , Kang Jieun , Kim Eun Ae , Jeong Seolhwa , Chae Yee Soo
Published: June 2024

e12577

Background: Cancer genomic sequencing has fundamentally advanced our understanding of the basic biology of this disease, and more recently, has offered method to guide and evaluate treatment in clinic. We performed whole-genome sequencing (WGS) on three consecutive tissue and blood samples from breast cancer patients: diagnosis, post-neoadjuvant chemotherapy, recurrence after curative resection. Methods: We performed WGS to compare the genetic profiles of the primary, surgical and recurrent samples (tissue and blood) to determine: (1) how closely related the genetics are among the primary, post-neoadjuvant chemotherapy, and the recurrent tumors, (2) whether there are variations in mutational processes among the primary, post- neoadjuvant chemotherapy, and recurrent tumor. WGS was performed on three patients for whom both tissue and blood were available at diagnosis, at surgery after neoadjuvant chemotherapy and at a recurrence. Results: As a result of somatic protein coding variant analysis, PIK3CA mutation was confirmed at the time of diagnosis tissue in all cases. Mutations were found at p.E545K in patient 14, p.R916C in patient 18, and p.R916C in patient 3. Among these, patients 14 and 18 had PIK3CA mutations even at the time of recurrence. In patient 14, the same PIK3CA mutation was found in 3 consecutive samples, but in patient 18, it changed from p.R916C at diagnosis to p.G480E at relapse. Furthermore, functional enrichment analysis identified a common NRAGE signaling system in the cfDNA. The NRAG pathway was found in the blood at diagnosis, surgery, and recurrence in all three patients. Conclusions: This study was a proof-of-concept study, in which we hypothesized that NRAGE/JNK and PI3K/AKT signaling pathways are involved in breast cancer recurrence and treatment response through WGS of consecutive samples. Further research is ongoing with larger numbers of patients.