bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world use of a CSF circulating tumor cell assay in the diagnosis and management of leptomeningeal metastasis.
Authors: Blondin Nicholas Alfred , Haberli Nicholas
Published: June 2024

2029

Background: The diagnosis of leptomeningeal metastasis (LM) can be challenging due to variability in clinical symptoms, radiographic, and cerebrospinal fluid (CSF) findings. The National Comprehensive Cancer Network (NCCN) guidelines recommend assessment of circulating tumor DNA (ctDNA) to increase sensitivity of tumor cell detection and assess the response to treatment. We hypothesize that the real-world use of an assay for the direct detection and enumeration of circulating tumor cells (CTCs) in the CSF is clinically useful for accurate diagnosis of LM, particularly in an early stage of disease. Methods: We report a series of 55 patients treated at our institution with a cancer diagnosis and either neurological symptoms or radiographic findings that suggested LM. All patients underwent a lumbar puncture, assessment for CSF CTCs, and conventional hospital-based cytology testing between 6/1/2020 and 8/1/2023. Survival data cutoff was 12/31/2023. Patient outcomes are reported. Results: 55 patients were tested, and 30 patients were found to be positive for CTCs and diagnosed with LM. Only 10 patients were concurrently positive for CTCs and cytology at our institution, whereas 20 patients with positive CTCs had a negative or ambiguous cytology. No patients with a negative CTC result (25 patients) were subsequently diagnosed with LM, whereas 4 patients with a positive CTC result remained without progressive neurological symptoms. 5 patients diagnosed with LM were alive at the time of data cutoff. The histologic breakdown for LM was: breast (11), non-small cell lung cancer (NSCLC) (16), gastrointestinal (GI) (3). Median overall survival (OS) was longer in patients with a positive CTC and negative cytology result compared to patients with concurrent positive CTC and cytology (172 vs. 63 days, p = 0.06). Median OS was also longer in breast cancer LM compared to NSCLC LM (235 vs. 63 days, p = 0.008). Most patients diagnosed with LM received therapies including Ommaya reservoir placement, intrathecal chemotherapy, and/or radiation. Conclusions: The use of a CSF circulating tumor cell assay aided the diagnosis of LM and led to timely initiation of treatment. A negative result of the CTC assay was associated with ruling out LM. Diagnosis of LM with the CTC assay and negative cytology was associated with longer survival, possibly due to earlier treatment initiation, and not solely a lead time bias. Breast cancer LM patients had improved survival compared to NSCLC and GI cancer patients, possibly due to more effective treatment options.
Intracranial hemorrhage in glioblastoma: Incidence, risk factors, and outcome.
Authors: Lee Seok-Yun , Devos Patrick , Bink Andrea , Regli Luca , Weller Michael , Le Rhun Emilie
Published: June 2024

2074

Background: The incidence and clinical implications of intracranial hemorrhage (ICH) in patients with glioblastoma have not been well studied. Risk factors for ICH and associations with therapy and outcome remain unknown. It has been speculated that prior radiotherapy, chemotherapy-associated thrombocytopenia, steroid medications as well as age, other comedications and comorbidities contribute to the risk of ICH in this patient population. Methods: We identified consecutive patients with glioblastoma per WHO 2021 definition from the electronic charts of the University Hospital in Zurich, Switzerland and explored the incidence, putative risk factors, management and outcome of ICH in patients with glioblastoma. ICH was identified on central MRI and imaging report review. The study has been approved by Swissethics (2023-00532). Results: Among 387 patients diagnosed between 2010 and 2019, 6 patients presented with ICH, and 22 patients experienced ICH in the further disease course, after a median time of 153 days (IQR 79-323 days). Of the 6 patients with ICH at diagnosis, 2 patients were on anti-platelet agents and 1 was on anticoagulation. ICH occurred in the tumor region in all these patients. There were no specific features in their history compared with patients that did not present with ICH at diagnosis. Among 22 patients with ICH after diagnosis, 9 patients (41%) experienced ICH prior to first progression. ICH were not restricted to the tumor region, but included subdural hematomas in 7 patients and an epidural hematoma in one patient. Fifteen patients (68%) were hospitalized for ICH, and 5 patients (23%) had a craniotomy. Thirteen patients (59%) had no change in management, 4 patients (18%) started a new intervention, and 5 patients (23%) went to palliative care. Compared with patients without any ICH ever documented, the 28 patients with ICH were more often male, but not older, did not have a history of arterial hypertension, diabetes, chronic kidney disease or smoking, and did not have larger tumors at diagnosis. At the timepoint of intracranial hemorrhage, six patients (27%) had been preexposed to bevacizumab, yet, 188 patients (53%) of the reference cohort received bevacizumab across the disease trajectory without experiencing an ICH. Three patients (14%) had platelet counts below 100,000/µl. Overall survival in the 28 patients who experienced an ICH was not inferior to survival in the population of patients without an ICH. Conclusions: ICH at diagnosis is rare in glioblastoma and its etiology remains to be identified. It may be related to intrinsic features of the tumor and its blood vessels since no other patient-related risk factors were identified. Overall, male sex was the only risk factor associated with ICH in this study, but ICH does not signify a poor outcome overall.
IOV-3001, a modified interleukin-2 fusion protein, for potential use in tumor-infiltrating lymphocyte cell therapy regimens.
Authors: Abelson Michelle R. , Johnson Sadie , Poprawski Joanna , Blauvelt Jamie L. , Hall Sean , Yin Hequn
Published: June 2024

2552

Background: Tumor-infiltrating lymphocyte (TIL) cell therapy has shown promising efficacy in patients with solid tumor malignancies. Interleukin-2 (IL-2) administration after TIL infusion supports persistence and survival of infused TIL. Aldesleukin is a synthetic IL-2 with a short half-life administered every 8–12 hours, to support the expansion and persistence of the TIL in vivo. IOV-3001 is a modified dimeric IL-2 fused to palivizumab that has a longer half-life and potentially better safety profile, compared with aldesleukin. Here, we describe the preclinical activity, pharmacokinetics (PK), pharmacodynamics (PD), and in vivo safety profile of IOV-3001. Methods: Binding of IOV-3001 and aldesleukin to the IL-2 receptor (IL-2R), IL-2R-mediated activation via STAT5 phosphorylation, and T cell proliferation were assessed. Pharmacological activities of IOV-3001 and aldesleukin were evaluated in B16-F10 mice infused with pmel-1 T cells. Safety after a single dose of IOV-3001 (0.01–9.0 mg/kg) was assessed in cynomolgus monkeys across 3 independent studies. PK and PD parameters, clinical pathology, hematology, and histopathology were assessed. Results: Both IOV-3001 and aldesleukin induced comparable STAT5 phosphorylation and proliferation of T-cell subsets. Mice infused with pmel-1 T cells and subsequently treated with IOV-3001 or aldesleukin showed similar reductions in tumor burden. The half-life of IOV-3001 in cynomolgus monkeys ranged from 5–8 hours. IOV-3001 was well tolerated in monkeys across the dose range studied except for 1 animal administered IOV-3001 at the highest tested dose level, with recovery by Day 29. Inflammatory cytokines (IL-12 p40, IL-6, MCP-1) increased from 4 hours to ≤3 days after dosing and returned to baseline by Day 29. Fibrinogen, bilirubin, and triglycerides increased on Day 3 and returned to baseline by Day 29. No signs of capillary leak were observed. Increased numbers of hematopoietic cells were found in the bone marrow, spleen, and lymph nodes 3 days post dosing. During the 4-week recovery, these changes diminished or resolved, while bone marrow showed differential dose-dependent effects. IL-2–induced proinflammatory PD effects were observed, including >10-fold peak CD8+ T cell expansion in peripheral blood mononuclear cells at Day 5 versus preacclimation in most cynomolgus monkeys treated with IOV-3001. Conclusions: IOV-3001 exhibited a similar mechanism of action (MoA) to that of aldesleukin in vitro and has a longer half-life in vivo. PD effects were consistent with the MoA of IL-2. IOV-3001 showed a favorable preclinical safety profile. These results suggest a potentially improved safety profile for IOV-3001 with less frequent dosing compared with aldesleukin. These features of IOV-3001 strongly advocate for its development in TIL cell therapy regimens.
Soluble mesothelin neutralizes mesothelin antibody-based therapies.
Authors: Smith Katherine Emilie Rhoades , Ayers-Ringler Jennifer , Dizona Paul , Lucien Fabrice , Kim Yohan , Orme Jacob , Winters Jeffrey , Moscow Jeffrey , Mansfield Aaron Scott
Published: June 2024

2565

Background: Mesothelin (MSLN) is overexpressed in mesothelioma and other solid tumors making it the focus of multiple targeted therapies, including antibody drug conjugates (ADCs), T cell receptor (TCR) fusion constructs, and chimeric antigen receptor T-cell (CAR-T) products. However, the clinical efficacy of these treatments remains limited. We hypothesize that soluble MSLN (sMSLN) in the plasma binds to MSLN-targeted therapies before reaching the tumor. Our study aimed to evaluate the effects of sMSLN on a MSLN-targeting antibody, anetumab, and explore methods to reduce sMSLN. Methods: Exploratory analysis in NCT03126630: sMSLN testing was performed on blood samples from participants enrolled in NCT03126630 at the Molecular Targets Core Lab, National Cancer Institute. The median was used to categorize high and low levels of sMSLN. Survival was estimated with the Kaplan-Meier method and compared between groups with the log rank test. Anetumab immunoprecipitation: Anetumab was covalently coupled to Dynabeads at 5 µg per mg of beads to immunoprecipitate MSLN from two plasma samples. Assays were performed in duplicate. Therapeutics plasma exchange (TPE):Whole blood samples were collected before and after one plasma volume of TPE with albumin as the replacement fluid in patients undergoing routine TPE for various medical conditions, such as autoimmune diseases and hyperviscosity syndromes. Plasma levels of sMSLN were measured with an ELISA assay in matched pre- and post-TPE plasma samples. Results: We obtained sMSLN levels from 40 patients enrolled in NCT03126630. For patients treated with both anetumab ravtansine and pembrolizumab, median progression free survival (PFS) was shorter in the high sMSLN group (5 months) vs the low sMSLN group (12 months). For patients treated with pembrolizumab alone, PFS was similar for patients with high and low sMSLN (4 vs 3.4 months). Anetumab significantly reduced the concentration of sMSLN in plasma samples as detected by MSLN ELISA (p<0.05), demonstrating that sMSLN can bind to and sequester anetumab. Next, we evaluated TPE as a mechanism to reduce sMSLN. We obtained pre- and post-TPE plasma samples from 15 patients undergoing routine TPE for various medical conditions. TPE consistently reduced sMSLN (p<0.05) with an average decrease of 43.6% or 15.4 ng/mL. Conclusions: We found that high sMSLN levels are associated with shorter PFS for anetumab ravtansine, but not pembrolizumab. Additionally, anetumab binds to sMSLN in the plasma, which suggests that sMSLN can sequester anti-MSLN antibodies and may limit the efficacy of MSLN-targeted therapies. High levels of sMSLN could potentially be used as a biomarker to select which patients should not receive MSLN-targeting therapies. Furthermore, our results indicate that sMSLN reduction is feasible with TPE. Decreasing sMSLN could restore the activity of MSLN-targeted therapies.
CD4 effector T cell expansion to identify objective responses to the CD40 agonist mitazalimab in combination with modified FOLFIRINOX (mFFX) as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC) in the OPTIMIZE-1 study.
Authors: Wattenberg Max Miller , Enell Smith Karin , Pico de Coaña Yago , Gomez Jimenez David , Ambarkhane Sumeet Vijay , Ellmark Peter , Beatty Gregory Lawrence
Published: June 2024

2569

Background: CD40 agonists have the potential to enhance the efficacy of standard of care chemotherapy and to trigger antitumor immunity. Preclinical models indicate that the success of this approach depends on appropriate sequencing of chemotherapy with a CD40 agonist. Preliminary efficacy results from the OPTIMIZE-1 Phase II study (NCT04888312) combining mitazalimab (anti-CD40) with mFFX chemotherapy in patients with mPDAC have been previously reported. Here, we investigated immunological determinants associated with favorable outcomes with this combination therapy. Methods: Newly diagnosed, chemotherapy-naive patients with mPDAC received mitazalimab (900 µg/kg) on day 1 prior to beginning an every 2-week mFFX regimen on day 8, followed by mitazalimab 48 hours later. Tumor response was determined using RECIST v1.1 criteria. Peripheral blood was analyzed for selected cytokines and chemokines and by flow cytometry to assess changes in leukocyte subsets including B cells, monocytes, T cells, and NK cells. Flow cytometric data from evaluable patients were subjected to unsupervised hierarchical clustering to identify immune subsets. A classifier was generated from an interim dataset (n=21) using a random forest model to predict cell populations and their association with tumor response, which were then applied to the full dataset (n=47). Results: Mitazalimab triggered an expected immune response characterized by transient cytokine (IFNg and MCP-1) release and B cell depletion. Chemotherapy caused a reduction in classical monocytes and proliferating CD4+ T cells. Both mitazalimab and chemotherapy caused a transient reduction in circulating dendritic cells and NK cells. Tumor response was associated with an expansion in the frequency of effector CD4 T cells (p < 0.0001) at day 8 after receiving mitazalimab. In a blinded analysis based on the classifier, CD4 T cell expansion was linked to an early tumor response to treatment (accuracy 70%, sensitivity 68%, specificity 72%). Conclusions: Mitazalimab and mFFX differentially modulate immune responses in patients with mPDAC. Pharmacological analyses identify mitazalimab-induced expansion of CD4 effector T cells one week after first administration as a correlate of treatment outcomes. These data suggest the contribution of mitazalimab to tumor responses, and further substantiate a priming dose of mitazalimab, prior to administering chemotherapy.
Transcriptome-based response predictor to identify potential responders among patients with negative standard markers for response to immune checkpoint blockers.
Authors: Dinstag Gal , Elis Efrat , Ben-Zvi Doreen S. , Elia Anna , Rajagopal Padma Sheila , Aldape Kenneth D. , Ruppin Eytan , Pikarsky Eli , Popovtzer Aron , Arnon Johnathan , Beker Tuvik , Aharonov Ranit
Published: June 2024

2666

Background: Immune checkpoint blockers (ICB) are revolutionizing cancer treatment, and are being approved for an increasingly wide range of cancer types. The most common biomarkers currently in use to select patients for ICB are PD-L1 expression on tumor cells, as measured by IHC, and tumor mutational burden (TMB) and microsatellite instability (MSI), both measured by NGS. However, some patients that are negative for these markers still respond to ICB. This calls for complementary biomarkers to better identify responders to ICB, especially in patients that are negative to current biomarkers. Here, we focus on predicting response to anti-PD1 in patients with negative PD-L1, TMB or MSI. Methods: We employ ENLIGHT, our transcriptome-based precision oncology platform, which identifies and utilizes clinically relevant genetic interactions to predict a patient’s response to a wide range of targeted drugs, including ICB. ENLIGHT generates an individual ICB response score calculated from a 10-gene expression signature - the ENLIGHT Matching Score (EMS). Patients with EMS above a predetermined threshold are considered matched by ENLIGHT to anti-PD-1 treatments. We have previously shown, based on more than 1000 cases analyzed retrospectively, that this signature can identify responders to anti-PD-1 with high accuracy. Here, we use ENLIGHT to perform a retrospective analysis of 125 cases from three different datasets, who had low PD-L1 presentation (<1%), low TMB (< 10) or microsatellite stable tumors (MSS), and were treated with anti-PD-1, to specifically assess ENLIGHT’s performance in this biomarker-negative sub-population. Results: Patients who responded to anti-PD-1 treatments had significantly higher EMS in all three datasets. Correspondingly, ENLIGHT is highly predictive of response to anti-PD-1 in patients with negative ICB markers in the three datasets (ROC AUCs of 0.80, 0.84, 0.77, respectively, for low PDL1, low TMB and MSS). It is important to note that ENLIGHT was not trained on any of these datasets, and is applied as-is using previously published parameters. Overall, we find that patients who are ENLIGHT-Matched to anti-PD1 in this biomarker-negative cohort are almost 3 times more likely to respond than patients who are not (31% vs. 11%, p=5e-13). Conclusions: ENLIGHT is a powerful tool for predicting response to anti-PD-1 treatment in patients with negative standard biomarkers for ICB, a currently unmet need with considerable clinical importance.
Phase I trial of talimogene laherparepvec for the treatment of peritoneal surface malignancies (TEMPO).
Authors: Stewart John H. , Lowe Melissa , Chapple Andrew G , Niedzwiecki Donna , Moyer Ashley , Bolch Emily , MacLaughlan Shannon Diane , Levine Edward A. , Moaven Omeed , Nettu Niharika , Strickler John H , Blazer Dan G.
Published: June 2024

2668

Background: Peritoneal surface malignancies (PSM) constitute a group of difficult-to-treat metastatic diseases that respond poorly to standard chemotherapy. Talimogene Laherparepvec (T-VEC), the first FDA-approved oncolytic virus (OV), demonstrates potential in treating various malignancies by effectively initiating crucial immune responses. Yet, the utility of intraperitoneal (ip) T-VEC for unresectable PSM is still unexplored. Methods: TEMPO (NCT03663712) was a nonrandomized, open-label, multicenter phase I trial involving 18 patients with unresectable PSM originating from the appendix (n=14), ovary (n=3), or small bowel (n=1). The trial aimed to determine the recommended Phase 2 dose (RP2D) and maximum tolerated dose (MTD) of ip T-VEC, as well as to evaluate its safety and tolerability. An exploratory endpoint was the Restricted Mean Survival Time (RMST), the estimated non-parametric mean survival time up until the longest patient follow-up time (i.e. maximum of the longest follow-up, and generally an underestimate of the actual mean survival time especially in small samples). Patients received an initial dose of 4x106 plaque-forming units (pfu) of ip T-VEC, followed by their assigned dose every two weeks for up to four additional doses, using a standard ‘3+3’ dose escalation scheme. The doses tested were 4x106, 4x107, and 4x108 pfu of ip T-VEC. Safety assessments were conducted regularly. Results: The RP2D is 4x108 pfu of T-VEC. The trial reported no dose-limiting toxicities, thus the MTD was not reached. Treatment-Related Adverse Events (TRAEs) were recorded and categorized by the maximum dose received (Table).One patient treated with 4x106 pfu had grade 3 abdominal pain and another grade 3 fatigue. No severe TRAEs occurred with 4x107pfu. One patient showed a grade 3 neutrophil count decrease at 4x108 pfu. The RMST, calculated with a truncation time of 5.5 months, varied across the doses. Patients receiving 4x106 pfu had an RMST of 3.1 (95% CI= 1.550-4.733) months, while those treated with 4x107 and 4x108 pfu had RMSTs of 4.2 (95% CI= 2.492-5.884) and 4.6 (95% CI= 3.551-5.722) months, respectively. Conclusions: We conclude that ip T-VEC is safe in patients with unresectable PSM. TEMPO successfully identified 4x108 pfu as the RP2D for TVEC. Notably, the RMST increased with increasing doses of TL. These results are promising, considering the limited benefit of conventional chemotherapy in treating PSM. This study positions T-VEC as a promising candidate for combination immunotherapies for PSM that amplifies the bystander immune response induced by OVs. Clinical trial information: NCT03663712 . [Table: see text]
FU/FA maintenance therapy with or without panitumumab (pmab) in RAS wild-type metastatic colorectal cancer (mCRC) (PanaMa, AIO KRK 0212): Updated efficacy analyses.
Authors: Modest Dominik Paul , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Müller Lothar , Koenig Alexander , Fischer von Weikersthal Ludwig , Caca Karel , Goekkurt Eray , Haas Siegfried , Kurreck Annika , Held Swantje , Jarosch Armin , Horst David , Reinacher-Schick Anke C. , Kasper Stefan , Heinemann Volker , Stintzing Sebastian , Trarbach Tanja , Stahler Arndt
Published: June 2024

3506

Background: The randomized open-label phase II PanaMa trial compared FU/FA with or without pmab maintenance after mFOLFOX6+pmab induction for RAS wild-type mCRC. Updated efficacy results of the Full Analysis Set are presented. Methods: Median progression-free survival (PFS), overall survival (OS), PFS of re-induction (PFS re-ind.), time to failure of strategy (TFS), and objective response rates (ORR) were compared by log-rank test / Cox regression and Fisher’s exact test. Results: PFS was significantly (8.8 vs. 5.8 months, HR=0.73 (95%CI 0.56 – 0.94), P=0.015) and OS numerically longer (29.9 vs. 24.7 months, HR=0.85 (95%CI 0.64 – 1.12), P=0.24). PFS re-ind. was significantly shorter after pmab maintenance (4.1 vs. 7.4 months, HR=1.93 (95%CI 1.33 – 2.82), P<0.001). TFS was comparable (17.1 vs. 15.7 months, HR=0.98 (95%CI 0.68 – 1.42), P=0.92). Molecular subgroups are displayed in Table 1. ORR of FU/FA+pmab was comparable to FU/FA during induction (74.4% vs. 76.4%, P=0.77), higher during maintenance (40.8% vs. 29.3%, P=0.06), but lower at re-induction (8.0% vs. 35.9%, P<0.001). Conclusions: PFS remained improved by the addition of pmab to FU/FA maintenance therapy, while OS was not significantly longer. Re-induction of pmab+mFOLFOX6 did not provide benefit following pmab maintenance regarding PFS. Clinical trial information: NCT01991873 . [Table: see text]
Candidate molecular alterations associated with potential resistance in KRAS G12D gastrointestinal cancers.
Authors: Jazieh Khalid , Tsai Jill , Solomon Sheila R , Xie Hao
Published: June 2024

3519

Background: KRAS G12D commonly occurs in pancreatic (PDAC) and colorectal (CRC) cancers. Though developing KRAS G12D inhibitors is pertinent, it is expected that primary and acquired resistance will limit efficacy, similar to those seen with KRAS G12C inhibitors. Here, we assessed the prevalence and outcomes of candidate mutations co-occurring with KRAS G12D in PDAC and CRC using liquid biopsy data. Methods: Patients with advanced CRC and PDAC tested with Guardant360 genomic profiling from 2020 to 2023 (~2500 & 3500 samples) were included. Candidate resistance mutations were determined based on mutations reported following KRAS G12C inhibition. Patients with advanced CRC and PDAC tested with Guardant360 at Mayo Clinic (2016-2023) (1158 & 904 samples) were assessed for overall survival (OS). Patients were divided into three groups: KRAS G12D alone, KRAS G12D with candidate resistance alterations, and KRAS G12D not detected (ND). OS was estimated using Kaplan-Meier method. Cox regression was used for multivariable survival analyses. Results: The Guardant360 database reported KRAS G12D in 16.5% of CRC and 40.2% of PDAC samples. The Table below summarizes the most frequent candidate resistance alterations co-occurring with KRAS G12Dincluding point mutations of KRASand PIK3CAand amplifications of EGFR, KRAS, BRAFand MYC. In the Mayo cohort, 8.9% of CRC and 23.5% of PDAC patients had KRAS G12D. In CRC, those with KRAS G12Dand ≥1 candidate resistance alteration had a significantly lower OS (mOS 18.7m) than KRAS G12D alone (30.9m), and ND (37.3m) ( p=0.004). The presence of concurrent candidate resistance alterations with KRAS G12D remained a poor prognostic factor with HR 2.1 (95% CI: 1.3 – 3.2, p=0.001) after adjusting for age and other patient characteristics. Similarly, in PDAC, those with KRAS G12D and ≥1 resistance mutation had significantly lower OS (mOS 8.1m) than KRAS G12D alone (10.5m) and ND (16.1m) (p<0.0001). In multivariable analyses, both KRAS G12D with candidate resistance alterations (HR 2.1, 95% CI: 1.4-3.3, p<0.001) and G12Dalone (HR 1.6; 1.3–2.0, p<0.001) were poor prognostic factors. Among patients with serial Guardant360, treatment response trended with KRAS G12D variant allele frequency. Conclusions: Circulating tumor DNA testing is a useful tool to reveal candidate molecular alterations linked to potential resistance to KRAS G12D targeting in patients with KRAS G12D gastrointestinal cancers. KRAS G12D with these concurrent molecular alterations is a poor prognostic factor in both PDAC and CRC. [Table: see text]
Cost-effectiveness analysis of later-line treatments for refractory metastatic colorectal cancer.
Authors: Cho Sang , Bekaii-Saab Tanios S. , Hocum Brian Thomas , Grossman Jamie , Appukkuttan Sreevalsa , Babajanyan Svetlana , Yang Min , Lee Woojung , Barzi Afsaneh
Published: June 2024

3525

Background: Recent clinical trials support regorafenib dose optimization (ReDO), a combination therapy with trifluridine/tipiracil and bevacizumab (TAS-BEV), and fruquintinib (FRUQ) for the treatment of refractory metastatic colorectal cancer (mCRC). This study evaluated relative cost-effectiveness of ReDO, TAS-BEV, and FRUQ for mCRC from a payer perspective in the United States. Methods: A Markov model was constructed to estimate total costs and quality-adjusted life years (QALY) for each treatment. In the base case, clinical parameters were obtained from the ReDOS study for ReDO, the SUNLIGHT study for TAS-BEV, and the FRESCO study for FRUQ. Economic parameters were obtained from IBM Micromedex RED BOOK for treatment costs and from the Centers for Medicare & Medicaid Services and the Agency for Healthcare Research and Quality for health care resource use. Incremental cost-effectiveness ratio (ICER) was used to evaluate relative cost-effectiveness of treatments. Model robustness was checked with deterministic (DSA) and probabilistic sensitivity analysis (PSA). A subgroup analysis was performed in patients with and without previous use of anti-VEGF therapy, but using the FRESCO-2 study for FRUQ because OS and PFS for this subgroup was unavailable in the FRESCO study. Results: In the base case, ReDO provided a higher QALY at a lower cost than TAS-BEV and FRUQ. During the first two months following treatment initiation, TAS-BEV had a higher total cost ($67,862) than ReDO ($44,695) and FRUQ ($48,688), partly due to the cost of managing neutropenia and using concomitant granulocyte colony stimulating factors (GCSF). The base case results were robust in DSA and PSA. Most influential parameters determining relative cost-effectiveness were related to treatment cost and effectiveness. In patients with previous anti-VEGF therapy, ReDO provided a higher QALY at a lower cost (0.571 QALY; $86,694) than TAS-BEV (0.490 QALY; $148,784) and FRUQ (0.411 QALY; $101,236). In patients without previous anti-VEGF therapy, TAS-BEV had a higher QALY (0.755 vs 0.571) and a higher cost ($232,701 vs $86,694) than ReDO, resulting in an ICER of $790,988 per QALY. Conclusions: ReDO was cost-effective compared with TAS-BEV and FRUQ, regardless of previous use of anti-VEGF therapy. In the base case, ReDO had a lower treatment cost than TAS-BEV and FRUQ, especially during the first month of dose optimization. TAS-BEV had the highest total cost, partly due to the cost of managing neutropenia and GCSF use. [Table: see text]
Combined amphiregulin and epiregulin expression as a prognostic and predictive biomarker of panitumumab (Pmab), fluorouracil, and folinic acid (FU/FA) or FU/FA maintenance therapy following Pmab+FOLFOX induction in RAS wildtype metastatic colorectal cancer (mCRC): PANAMA trial (AIO-KRK-0212).
Authors: Stahler Arndt , Hoppe Beeke , Keilholz Luisa , Na Il-Kang , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Fischer Von Weikersthal Ludwig , Kasper Stefan , Ballhausen Alexej , Sommerhäuser Greta , Alig Annabel Helga Sophie , Kurreck Annika , Held Swantje , Heinemann Volker , Horst David , Jarosch Armin , Stintzing Sebastian , Trarbach Tanja , Modest Dominik Paul
Published: June 2024

3528

Background: mRNA expression of amphiregulin ( AREG) and epiregulin ( EREG) as ligands of the epidermal growth factor receptor (EGFR) were associated with response to anti-EGFR directed antibodies in metastatic colorectal cancer (mCRC). Their role for maintenance treatment remained unclear yet and was investigated in the PanaMa trial (panitumumab (Pmab) and fluorouracil/folinic acid (FU/FA) vs. FU/FA alone after Pmab+FOLFOX induction therapy in RAS wild-type mCRC). Methods: Gene expression was measured after mRNA isolation in 196 of 248 patients of the full analysis set. The analysis was conducted using a customized Nanostring PanCancer Progression Panel. AREG and EREG mRNA expression was dichotomized by median. High combined expression was defined as mRNA expression of AREG and EREGequal or above the median. Median progression-free (PFS) and overall survival (OS) since start of maintenance were estimated by Kaplan-Meier-method and Cox-regression, using the log rank test. Objective response rates (ORR) of maintenance therapy were compared by Fisher’s exact test. Treatment interaction was tested by Cox regression. Results: In 196 patients with available mRNA expression data, high AREG, EREG and combined AREG / EREG expression were observed in 103 (52.6%), 97 (49.5%) and 84 (42.9%), respectively. Regardless of treatment, high combined AREG / EREG expression was associated with prolonged PFS (7.7 vs. 5.8 months, HR 0.69 (95% CI 0.51 – 0.93), P=0.016), OS (30.1 vs. 24.4 months, HR 0.58 (95% CI 0.41 – 0.82), P=0.002) and increased ORR of maintenance treatment (39.3% vs. 28.6%, P=0.13), compared to low expression. Tumors with high combined AREG / EREG expression were associated with numerical longer PFS, OS and higher ORR when treated with Pmab+FU/FA maintenance (Table). Significant interaction of combined AREG / EREG expression with treatment was observed in terms of PFS ( P=0.003) and OS ( P=0.016). Conclusions: Combined AREG and EREG mRNA expression was confirmed as prognostic biomarker for mCRC patients receiving maintenance treatment. Efficacy of maintenance treatment might potentially be higher for Pmab+FUFA maintenance in mCRC with high combined AREG / EREG expression in the PanaMa trial. [Table: see text]
A novel, noninvasive, multimodal screening test for the early detection of precancerous lesions and colorectal cancers using an artificial intelligence–based algorithm.
Authors: Turgeon D. Kim , Krammes Lena , Mahmood Hiba-Tun-Noor , Frondorf Friederike , Königs Vanessa , Luther Julia , Schölz Christian , Becker Patrick , Maharjan Srijana , Sever Ayfer , Garapati Santhi , Balasubramaniam Anujan , Knabe Martin , Sharma Guddi , Pham Trung , Preywisch Regina , Eidens Moritz , Bresalier Robert , Dollinger Matthias
Published: June 2024

3627

Background: Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality worldwide, and its incidence is increasing in younger populations. Detection of early-stage CRC and its precursor lesions, such as advanced adenomas (AA), is crucial for successful treatment and reduces CRC-related mortality. Although non-invasive methods for early detection are available and increase screening compliance, their performance with respect to detection of advanced adenomas and early-stage cancers is limited. Here, we describe a novel and non-invasive stool-based approach combining diagnostic biomarkers with an algorithm generated by machine learning/artificial intelligence (ML/AI) resulting in significantly improved diagnostic performance for the detection of not only CRC, but especially precancerous lesions like AA. Methods: Data were generated from a combined cohort of stool samples collected at 10 clinical sites in Europe (COLOFUTURE study) and 21 clinical sites in the US (eAArly DETECT study). The evaluable study cohort consists of 690 subjects, including 78 CRC, 146 AA, 147 with non-advanced adenoma (AD) and 319 normal colonoscopy negative control (NC) subjects (49% female, 51% male, average age 61.8 years). Results were compared with colonoscopy and pathology findings to determine sensitivity and specificity for detection of early-stage CRC and AA vs. AD and NC. Nucleic acids were extracted from stabilized stool samples using a silica bead-based extraction method. Expression of mRNA biomarkers was analyzed utilizing Real-Time PCR. Human hemoglobin was quantified using FIT. The Emerge Quantitative Evolution ML/AI platform was leveraged to develop classifiers capable of distinguishing CRC and AA from AD and NC. Results: Applying the combined approach of non-invasive diagnostic testing with an AI/ML generated algorithm, the sensitivity for detection of CRC overall was 92.3%. In addition, this method enabled AA detection with a sensitivity of 82.2%. Specificity turned out to be 90.1 % (AD+NC). Conclusions: This innovative, non-invasive, multimodal screening strategy based on self-collected stool samples which combines mRNA expression patterns and FIT analysis with an AI/ML-generated algorithm represents a substantial improvement in the effectiveness of non-invasive CRC screening. Such improvements in usability and performance leading to reliable detection of early-stage CRC and precursor lesions, such as advanced adenomas, are required for wide-spread availability and adaption of non-invasive screening tests to accepted clinically relevant usage and to prevent the development of CRC effectively.
Advancements in breast cancer progression monitoring: Analysis of methylated circulating cell- free DNA.
Authors: Hung Chin-Sheng , Lin Ruo-Kai
Published: June 2024

e12548

Background: Breast cancer is a leading cause of mortality among women, with a significant number developing metastasis. Existing markers like CA-153 and CEA have limited sensitivity. Circulating cell-free DNA (ccfDNA) in plasma can be used for the noninvasive sampling of cancer cells obtained from patients with breast cancer. Aberrant circulating methylated GCM2 and TMEM240 have been reported in patients with breast cancer. The study aims to evaluate the potential of simultaneous detection of methylated GCM2 and TMEM240 in plasma for enhanced prediction of residual disease and tumor progression. Methods: In a prospective study conducted in Taipei, Taiwan, we enrolled a total of 396 patients between 2016 and 2023. The retrospective study involving plasma samples from Western populations included a total of 134 samples. Utilizing the Monte Carlo replicates module within the R software, is employed to automate the random partitioning of 70% of the entire patient dataset into a training set, while the remaining 30% is assigned to the validation set. The model's performance, including sensitivity, specificity, accuracy, false positives, and false negatives, will be thoroughly assessed to ensure its robustness. Results: The test demonstrated an accuracy of 91.5%, a sensitivity of 95.7%, and a specificity of 90.3% for prediction of residual disease and tumor progression. CA15-3 and CEA markers show limited sensitivity (53.3% and 33.3%, respectively). The tests also assess the tumor burden dynamically through monitoring circulating methylated GCM2 and TMEM240 in plasma of patients with breast cancer following their treatment. Conclusions: The simultaneous detection of circulating methylated GCM2 and TMEM240 in plasma presents a novel and accurate noninvasive tool for predicting tumor progression. Clinical trial information: N201708049, N202105091, N202202061.
The role of obesity in the clinicopathologic variables and treatment of early stage breast cancer.
Authors: Bello Andreas , Nashed Rebecca , Wable Devanshi Girish , Makani Neeharika Srivastava
Published: June 2024

e12555

Background: Breast cancer (BC) is the second most common cancer among women in the United States. Studies have found obesity to be a key risk factor for BC, in which obese patients have higher recurrence and mortality. With 40% of the United State population being obese, we studied the differences in clinicopathological variables and treatment of normal-weight (NW) and obese patients with BC in a community-based cancer center within Florida. Methods: In this retrospective study, 535 patients with non-metastatic breast cancer (NMBC) diagnosed between January 1st, 2015 and December 31st, 2021 were identified. A Two Proportion Z test was done to evaluate the association between body mass index (BMI) groups of NW (BMI <25) and obese (BMI >30) patients amongst several independent variables. Variables included are histology, grade, estrogen and progesterone receptor status (ER/PR), human epidermal growth factor receptor 2 (HER2) status, chemotherapy, and surgical modality. Results: Results demonstrated that only Grade 2 histology was statistically more prevalent in NW vs obese patients (p < 0.01). 218 patients underwent mastectomy with 54% in the obese BMI. 317 patients were treated with lumpectomy with 65% in the obese BMI. Of the 211 NW patients, 97% were HER2 negative or low compared to 96% in the obese group. Only 3% and 4% of patients were HER2 positive in NW and obese groups, respectively. Of the obese patients, 40% were treated with neoadjuvant/adjuvant chemotherapy compared to 33% of NW patients (p=0.05). Factors such as mean age, smoking status and other demographic information were not statistically different between the groups. Conclusions: This study demonstrates that obese NMBC patients required chemotherapy more often than NW patients and that histologic characteristics cannot explain this difference in treatment. Factors such as stage at diagnosis or BC prognostic scores may contribute to the increased use of chemotherapy in obese patients. A limitation of this study is that the stage of disease at diagnosis was not abstracted, as a new staging system for BC was implemented in 2018. Furthermore, studies have suggested that, in obese patients, difficulty in identification of a mass in clinical or self -breast exam and poor compliance with screening guidelines may delay diagnosis of BC at an earlier stage. Obesity has many negative health effects, and with the increased use of novel weight loss medications, it will be important in the future to study the impact this may have on breast cancer development, histopathologic features, and treatment of patients with breast cancer. [Table: see text]
Characterizing the 70-gene MammaPrint risk stratification in Chinese luminal type breast cancer and its correlation with clinicopathological characteristics, immune and metabolic functions.
Authors: Pan Ruilin , Lin Jiawei , He Tiancheng , Liu Chun , Wang Ciran , Zheng Hongbo , Ye Guolin
Published: June 2024

e12559

Background: The 70-gene MammaPrint is endorsed by the NCCN guidelines for predicting 5-year distant metastasis risk in HR+, HER2-, with 0-3 lymph nodes, early invasive breast cancer. Similarly, it is recommended by the CSCO breast cancer guidelines for prognostic assessment post breast cancer surgery. However, no prior studies have investigated its application in Chinese luminal-type breast patients or its correlation with immune and metabolic functions. Methods: This analysis encompasses 76 early-stage invasive Luminal breast cancer patients, registered at the First People's Hospital of Foshan between 2020 and 2023, with recorded clinical characteristics under informed consent. Patient-reported data include clinical features, pathology, and the 70-gene MammaPrint risk of recurrence. Additionally, RNA-seq analysis was conducted in 24 patients. Results: Among 76 enrolled patients,55.3% were categorized as MammaPrint low risk (MP-Low), and 44.7% as MammaPrint high risk (MP-High). Patients over 50 were more likely MP-Low (p=0.028, OR=2.860), while those with >20% Ki67-stained cells were prone to MP-High (p<0.001, OR=0.160). Comparing with MINDACT, there was 52.3% consistency, with 55.6% of MP-Low patients being C-Low (MINDACT risk Low) and 47.1% of MP-High patients being C-High (MINDACT risk High). Notably,21% of C-Low patients showed MP-High risk, and 27% of C-High patients exhibited MP-Low risk, of which 83.3% were ≥50 years old. Based on MINDACT and ISPY2 trial outcomes, patients were further categorized into four groups: MP-Ultralow, MP-Low but not ultralow (LNUL), MP-High but not ultrahigh (HNUH) and MP-Ultrahigh. The study identified an 18% MP-Ultralow population, suggesting that excessive adjuvant therapy might be avoided in these patients. Additionally, 41% of patients were identified as LNUL group, indicating potential benefit from adjuvant treatment or endocrine prolongation therapy. 4% were identified as MP-Ultrahigh group, suggesting potential benefits from neoadjuvant targeted therapy, albeit a poorer long-term benefit in the non-pCR portion. Further transcriptome analysis in 24 patients revealed significantly higher levels of Th2 cells in the MP-High group, with no significant difference observed in CD8 T cells between the two groups. Meanwhile, metabolic-related signatures also differed, with significantly higher levels of Dopamine, Norepinephrine, Heme, and Epinephrine biosynthesis in the MP-Low group. Conclusions: This study elucidates the intricate relationships between MammaPrint prediction results of 70 genes and clinical characteristics, immune and metabolic signatures in Chinese Luminal type breast cancer patients. The refined risk classification provides valuable insights for precision treatment, advancing personalized therapeutic strategies.
Mechanism study on fig exosome-like nanoparticles inhibiting the progression of bone metastasis in breast cancer.
Authors: Wang Dandan , Tian Hao , Qian Jin , Zhao Tingting , Sun Na , Mei Zifan , Peng Zaihui , Zhang Yi , Kang Xia , Qi Xiaowei
Published: June 2024

e12562

Background: Breast cancer has overtaken lung cancer as the most common cancer worldwide. Breast cancer bone metastases can lead to death. How to inhibit the progression of bone metastasis of breast cancer is the key to improve the quality of life of breast cancer patients. In recent years, there have been increasing studies on the therapeutic significance of plant-derived extracellular vesicles (PDEVs), which play an important role in anti-tumor and anti-inflammatory. It is a new potential anti-tumor therapy. According to the Chinese medicine classics, figs have anti-cancer effect, but the main active ingredients are not clear yet. Methods: The exosomes were extracted by differential ultracentrifugation. The breast cancer cells (MDA-MB-231, MCF-7, 4T1, E0771) were treated with 0.1 ug/ml and 0.5 ug/ml fig exosome-like nanoparticles (FELNs) for 48 hours. The proliferation rate was measured by BrdU kit and verified by RT-qPCR. The total RNA from MDA-MB-231 cells treated by FELNs was sequenced to screen the differential genes. Key genes were differentially expressed in MDA-MB-231 and MCF-7 cells and further verified. Animal models of breast cancer in situ and bone metastasis were constructed in mice. FELNs were injected intraperitoneally twice a week, live imaging of small animals was performed on the 14th and 21st day to observe the tumor size and progression of breast cancer, and tibia samples were collected for Trap staining. The bone marrow macrophages of mice were extracted and treated by FELNs. The polarization was detected by RT-qPCR. After the removal of the proteins and nucleic acids in FELNs by protease, DNase and RNase, FELNs intervened in breast cancer cells and macrophages to determine the effective components of the FELNs. Results: After breast cancer cells were treated with FELNs, the proliferation rate was significantly decreased, especially MDA-MB-231 (from 70.3% to 17.7%) and MCF-7 (from 7.32% to 1.63%), and the RNA level of proliferation-related gene were significantly down-regulated. The key gene RN7SL1 was screened by sequencing. Overexpression of RN7SL1 significantly promoted the proliferation of MDA-MB-231 and MCF-7 cells, while the level of proliferation-related gene RNA was significantly up-regulated. FELNs significantly inhibited the tumor size and bone metastasis of breast cancer, and the tibial osteolysis was significantly abated by the treatment of FELNs in tibial Trap staining. After the intervention of FELNs in mouse macrophages, the polarization of M1 macrophages was significantly promoted. The proliferation rate of breast cancer cells increased and the polarization of M1 macrophages disappeared by treatment with protein-free FELNs. Conclusions: The protein components in FELNs inhibit the proliferation of breast cancer cells through RN7SL1, thereby inhibiting the progression of breast cancer bone metastasis.
Prediction of pathological response to neo-adjuvant chemotherapy using texture parameters of initial 18-FDG PET/CT in estrogen receptor positive/Her2 negative (ER+/HER2-) early breast cancer (eBC).
Authors: Corda Hugo , Lasla Hamza , Guillerminet Camille , Lacombe Marie , Girault Sylvie , Campone Mario , Frenel Jean-Sebastien , Jézéquel Pascal , Patsouris Anne
Published: June 2024

e12567

Background: ER+/HER2- phenotype represents 70% of eBC and is itself a heterogenic entity in which neoadjuvant chemotherapy (NAC) can be indicated. Early change in 18F-FDG uptake on PET/CT, using standardized uptake value (SUV) parameter, has been shown as a predictive biomarker of response to NAC. However, this parameter can be defaulted in ER+/HER2- BC. The objective of this work was to evaluate the correlation of textural parameters of initial 18-FDG PET/CT with histologic response in ER+/HER2- eBC. Methods: All patients receiving NAC for ER+/HER2- eBC, with 18F-FDG PET/CT prior NAC at the Integrated Center for Oncology Pays de Loire were included between 2012 and 2023. Twenty-nine metabolic and volumetric parameters and 42 textural features (DOSISOFT software, Planet Onco v2.0) were collected. Pathological response was assessed for each breast tumoral lesion in case of multifocal disease. Results: A total of 161 patients with 179 lesions were included. Medium age was 51 years old. 89% and 10% of patients presented a cT1 or cT2 tumoral lesion, 78% with lymph node involvement, 44% with a grade 3 and 46% with a HER2 low status. 21% of patients achieved a pathological complete response in breast (ypT0) and 11% a complete histologic response (ypT0N0). Examinations were performed using three types of PET/CT systems (GE Healthcare and Philips Healthcare). In order to harmonize radiomics data Combat method was used. Thirteen semi-quantitative (MTV and SUVmax, SUVmean, SUVmean(EVPc), SUVpeak, TLG for weight-normalized and lean-body-mass-normalized, respectively) and 6 textural parameters (entropy, homogeneity, SRE, LRE, LGZE, and HGZE) were retained. For all radiomics features used in this study, no statistical difference was found between ypT0 and non-ypT0 patients (p ≥ 0.05). Conclusions: Selected textural parameters were not associated with histologic response in our cohort of ER+/HER2- eBC. However, many other textural features, not retained in this study because influenced by acquisition parameters and segmentation methods, could be taken into account. An ongoing preliminary work (as resampling, normalization) is needed to improve their robustness before evaluating their interest in predicting histologic response to NAC.