bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.