bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real world effectiveness of regorafenib in heavily pretreated patients with metastatic colorectal cancer.
Authors: Danilova Anastasia , Stroyakovsky Daniil , Kanner Dmitry , Chernikovksy Ilya , Savelov Nikita , Volkonsky Mikhail , Demidova Irina 
Published: January 2024

141 Background: Metastatic colorectal cancer (mCRC) remains a challenge with a significant impact on patient survival and quality of life. Over the past decade, targeted therapies have emerged as promising treatment options for mCRC, including regorafenib. While clinical trials have established efficacy and safety of regorafenib in mCRC, based on the CORRECT and ReDos trials, the real-world utilization and outcomes associated with this therapy have gained increasing importance. This abstract presents a real-world data analysis focused on the use of regorafenib in patients with metastatic colorectal cancer in a community based comprehensive cancer center in Moscow, Russia. The data were collected from 2 outpatient medical oncology departments from 2018-2022 and we evaluated the real world patterns of use, effectiveness and safety. Methods: We evaluated all patients who were issued Regorafenib at a medical pharmacy of our cancer center. We evaluated all Regorafenib issued from 2018-2022 in our center – 348 patients received Regorafenib and 311 of them were patients with metastatic colorectal cancer and identified patterns of use, toxicity and outcomes in this patient population. Results: The median age was 61.2 and 49.5% were female (50.5 – were male%) Primary tumor was right sided in 20.9% of all patients, left sided – 49.1% and rectum in 29.9% De novo metastatic colorectal cancer was in 208 patients and 103 patients were those who progressed after initial treatment. Mutation status was identified in 91% of all patients. 46% had KRAS mutation, 3.8% were BRAF mutated and 4.2% were NRAS mutated. MSI status was known for 71% of the patients and it was negative. We understand the selection bias, because most of MSI-h patients would have gone on to receive immunotherapy rather than a TKI. The patients identified in our practice were more heavily pretreated (93.5% of them received more than 3 lines of prior therapy) and 1/3 of all patients were ECOG 2-3 performance status. Toxicity data were available only in 61% of the patients which reveals data caveats when using real world data outside of a clinical trial. Any grade toxicity was noted in 53% of all patients. Using Kaplan Myer Survival Analysis, the median PFS was 2 months and median OS was 5.3 months in the evaluated population. Conclusions: The real world data analysis shows that while Regorafenib is another treatment option, and our data confirm the results of clinical trial, its utilization and use provides only modest clinical benefit for patients.[Table: see text]
Impact of early tumor shrinkage and depth of response in patients with BRAF V600E-mutant metastatic colorectal cancer.
Authors: Udagawa Shohei , Osumi Hiroki , Ooki Akira , Wakatsuki Takeru , Fukuoka Shota , Yoshino Koichiro , Tamba Mikako , Ogura Mariko , Takahari Daisuke , Chin Keisho , Yamaguchi Kensei , Shinozaki Eiji 
Published: January 2024

142 Background: Early tumor shrinkage (ETS) and the depth of response (DpR) are early on-treatment surrogate markers for survival in patients with metastatic colorectal cancer (mCRC) receiving anti-epidermal growth factor receptor (EGFR) monoclonal antibody. However, the utility of ETS and DpR for BRAF V600E mutant (MT) mCRC which has a poor prognosis remains unclear. The aim of this study is to evaluate the association between ETS and DpR and clinical outcomes in BRAF V600E MT mCRC. Methods: mCRC patients who were diagnosed BRAF V600E MT and treated with 1st line chemotherapy from June 2011 to March 2023 at single cancer institute were enrolled. We analyzed the association between ETS and DpR and clinical outcome in patients who had at least one target lesion. Subgroup analysis of clinical factors related to progression free survival (PFS) and overall survival (OS) was performed using multivariate analysis. ETS was defined as the relative change in the sum of the longest diameters of RECIST target lesions at first follow-up CT scan compared to baseline and DpR was defined as the relative change in the sum of the longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline. Results: In total, 54 patients of BRAF V600E MT mCRC had at least one target lesion. In total of StageI-IV CRC patients, the incidence of BRAF V600E MT was 6.3% (233/3705). Patients with ETS ≥ 20% and DpR ≥ 25% (median value) were 24 (44.4%) and 27 (50%) respectively. PFS was 7.5 months (95% confidence interval (CI), 5.0-9.9) and OS was 17.1 months (95% CI, 11.7-20.2). Patients with ETS ≥ 20% had longer PFS and tended to have longer OS than those with non-ETS, with a median PFS of 9.8 months vs. 4.8 months (P Log-rank = 0.048, hazard ratio (HR), 0.55; 95% CI, 0.30-1.00), and a median OS of 22.6 months vs. 11.6 months (P Log-rank = 0.18, HR, 0.67; 95% CI, 0.37-1.21). Patients with DpR ≥ 25% had also longer PFS and OS than those with non-DpR, with a median PFS of 11.0 vs. 4.3 months (P Log-rank < 0.01, HR, 0.36; 95% CI, 0.20-0.66) and a median OS of 22.6 vs. 10.1 months (P Log-rank = 0.047, HR, 0.55; 95% CI, 0.31-1.00). Median time to DpR was 3.05 months. In multivariate analysis, DpR was significantly associated with both longer PFS (HR: 0.27, 95% CI: 0.14–0.55, P < 0.01) and OS (HR: 0.52, 95% CI: 0.29–0.96, P = 0.04). Conclusions: ETS and DpR may be early surrogate markers for clinical outcome in BRAF V600E MT mCRC who were treated with 1st line chemotherapy.
Consistency and heterogeneity of microsatellite instability (MSI) status in paired biopsy and surgical specimens of colorectal cancer: A necessity for MSI reassessment after treatment?
Authors: Tang Yuan , Cui Wei , Shi Shanshan , Sun Linyong , Wei Baoye , Liu Fei , Xi Yanfeng , Xie Bin , Zhang Zhihong 
Published: January 2024

149 Background: Microsatellite instability (MSI) plays a crucial role as a cancer immunotherapy and prognosis biomarker, making accurate MSI detection essential. However, currently, there is still a lack of available data on the impact of neoadjuvant therapy on MSI status, as well as validated data on standardized methods for MSI testing in small biopsy samples. The study aimed to investigate the concordance of MSI status between paired biopsy and surgical samples, as well as the impact of neoadjuvant therapy on MSI status using a novel MSI next-generation sequencing (MSI-NGS) detection panel. Methods: A total of 137 colorectal cancer (CRC) patients were enrolled for this study, of whom 116 with paired biopsy and surgical samples were analyzed. A custom MSI-NGS panel was employed and its performance was compared to MSI polymerase chain reaction (MSI-PCR), which served as the gold standard. Results: Out of the 116 cases, 112 patients showed consistent MSI status between biopsy and surgical samples, with an overall accuracy of 97% regardless of the detection method used. In the cases with MSI discrepancy (6 cases), 83% (5/6) of the patients showed a transition from MSS to MSI-H from biopsy to surgery. Interestingly, all eight patients who received neoadjuvant chemotherapy maintained an unchanged MSI status. However, in one patient who received adjuvant treatment and underwent a repeat biopsy after surgery, the MSI status exhibited alterations. Further analysis of clonal evolution revealed that this heterogeneity stemmed from the disappearance of the original clones and the emergence of new clones. Additionally, the NGS panel exhibited strong concordance with MSI-PCR and high accuracy, sensitivity and specificity with an AUC of 0.942 after rigorous validation. Conclusions: The study revealed a high concordance in MSI status between paired biopsy and surgical samples by employing a custom MSI-NGS panel for MSI status detection, providing reliable basis for further research in this field. Moreover, neoadjuvant chemotherapy seemed to have no impact on MSI status in our study, whereas postoperative adjuvant chemotherapy may influence changes in MSI status, highlighting the necessity of reevaluating MSI status after surgery. The findings also underscore the potential of NGS-based MSI detection as a valuable tool for clinical decision-making.
Clinical utility of upfront circulating tumor DNA (ctDNA) genotyping to guide first-line therapy in patients (pts) with metastatic colorectal cancer (mCRC): A GOZILA substudy.
Authors: Aoki Yu , Nakamura Yoshiaki , Komatsu Yoshito , Taniguchi Hiroya , Sunakawa Yu , Shiozawa Manabu , Kitagawa Chiyoe , Ohta Takashi , Matsuhashi Nobuhisa , Yamazaki Kentaro , Boku Shogen , Takahashi Naoki , Esaki Taito , Kawakami Hisato , Kagawa Yoshinori , Nishina Tomohiro , Yamaguchi Kensei , Bando Hideaki , Yoshino Takayuki 
Published: January 2024

157 Background: The clinical utility of upfront ctDNA genomic profiling is not established in treatment (tx)-naïve pts with mCRC. Methods: GOZILA is a nationwide plasma genomic profiling study using Guardant360 CDx for advanced solid tumors. We assessed ctDNA molecular profile and its association with treatment efficacy in pts with mCRC who were enrolled in GOZILA from January 2018 to July 2022 and underwent ctDNA genotyping before initiation of first-line systemic tx. ctDNA fraction was defined as the maximum variant allelic frequency of somatic alteration and pts were classified into three groups based on ctDNA fraction: low (<1%), middle (≥1% and <10%) and high (≥10%) ctDNA fraction groups. Results: This study included 418 pts with mCRC receiving upfront ctDNA genotyping. Median turnaround time of ctDNA test was 7 days, comparable with standard-of-care (SOC) tissue RAS/BRAF testing (7 days) and microsatellite instability (MSI) testing (8 days). Pathogenic alterations were detected in 384 pts (92%), and concordance rates for RAS and BRAF mutation (mut) compared to SOC tissue-based testing were 91% and 97%, respectively. Based on biomarkers identified by ctDNA genotyping, 142 (40%) pts were treated with matched targeted tx: anti-EGFR antibody for RAS/BRAF wild-type (n=137), BRAF inhibitor for BRAF V600E mutation (n=4), and anti-PD-1 antibody for MSI high (n=1). Low, middle, and high ctDNA fraction groups included 87, 97 and 234 pts, respectively, and had significantly different median progression-free survival (PFS) (p<0.01, table) and overall survival (OS) (p<0.01, table), respectively. In 13 pts who repeated ctDNA test before second-line tx, those with elevated ctDNA fraction compared to upfront ctDNA had significantly shorter PFS (median, 3.8 vs. 8.1 months; HR, 5.7, 95% CI, 0.9 to 35.1) and OS (median, 8.2 vs. 17.4 months; HR, 11.3, 95% CI, 1.2 to 105.9) of second-line tx that those with not elevated ctDNA fraction. Conclusions: Upfront ctDNA genotyping successfully identified actionable genomic alterations in pts with mCRC. ctDNA fraction in upfront ctDNA was significantly associated with efficacy of first-line tx and ctDNA fraction monitoring may be useful in determination of subsequent tx. [Table: see text]
Real-world evaluation of clinical outcomes and long-term survivors in patients with BRAF-V600E metastatic colorectal cancer.
Authors: Phillips William , Alrehaili Mohammad , Marginean Horia , Asmis Tim , Vickers Michael M. , Lo Bryan , Goodwin Rachel Anne 
Published: January 2024

166 Background: BRAF-V600E mutant metastatic colorectal cancer (BRAF-V600E mCRC) is associated with poor prognosis but confers response to combination BRAF/EGFR blockade. The goal of this study is to evaluate the clinicopathologic features and natural history of BRAF-V600E mCRC in the era prior to combination BRAF/EGFR inhibitors. Methods: This is a retrospective study of patients treated at the Ottawa Hospital Cancer Centre with BRAF-V600E mCRC who did not receive combination BRAF/EGFR therapy. Patients diagnosed with colorectal cancer prior to March 31, 2021, were included. Demographic, clinical, pathologic and cancer characteristics were abstracted from electronic medical records. Outcomes of interest included duration of therapy, as a surrogate of progression free survival, and overall survival (OS). Long-term survivor was defined as OS greater than 2 years. Results: 74 patients were included. Median age was 70 years (IQR=61-78), and 39 (53%) patients were female. There were 17 (23%) patients alive at the end of the follow-up period. 31 (42%) patients had poorly differentiated grade and 26 (35%) were mismatch repair deficient (dMMR). Locations of metastases included liver (40, 54%), peritoneum (30, 41%), lung (18, 24%), bone (5, 7%) and brain (5, 7%). Overall, 64 (86%) patients received first line systemic therapy, 19 (26%) second line, and 5 (7%) third line (see Table). Median duration of therapy in the first line was 4.3 months (IQR=2.0-9.6), second line was 2.9 months (IQR=1.4-4.1), and third line 1.0 months (IQR=1.0-1.9). Overall survival in the entire cohort was 13.2 months (IQR=4.6-25.4). Importantly, 21 (28%) patients were long-term survivors, of which 8 (11%) were dMMR. Conclusions: Patients with BRAF-V600E mCRC generally have poor clinical outcomes with traditional systemic therapies. In this study, we identified approximately 25% of patients who are long-term survivors (OS >2 years). This reflects the real-world heterogeneity of clinical outcomes for patients with BRAF-V600E mCRC who did not receive BRAF/EGFR targeted therapy.[Table: see text]
Association of candidate alterations with primary resistance to KRAS G12D targeting in colorectal cancer.
Authors: Jazieh Khalid , Tsai Jill , Zhu Mojun , Xie Hao 
Published: January 2024

170 Background: KRAS-mutant colorectal cancer (CRC) has a worse prognosis and greater resistance to therapy, attracting tremendous efforts to develop both allele-specific and pan-KRAS targeting agents including KRAS G12C and G12D inhibitors. CRC has demonstrated both primary and acquired resistance to KRAS G12C inhibitors, which can be better evaluated by circulating tumor DNA (ctDNA)-based next generation sequencing (NGS) methods without tissue sampling bias. Here, we utilized clinical ctDNA data to delineate the landscape of candidate alterations associated with primary resistance to KRAS G12D targeting in CRC. Methods: Samples from advanced CRC patients with Guardant360 data in 2021 were categorized into a KRAS G12D group and comparator groups of KRAS G12C and KRAS not detected (ND) according to KRAS mutation status. Demographics, MSI-H status, and blood tumor mutational burden (bTMB) were summarized and compared between groups using t-test for continuous variables and Fisher’s exact test for categorical variables. Co-occurrence patterns of alterations between KRAS and other genes were assessed. Primary resistance mutations were inferred by acquired resistance findings to KRAS G12C inhibitors reported by Awad et al. N Engl J Med. 2021 and Tanaka et al. Cancer Discov. 2021. Results: Among approximately 2500 samples, 16.8% had KRAS G12D, the most common KRAS mutation in CRC. The mean allele frequency of KRAS G12D (11.4%) is comparable to that of KRAS G12C (10.9%). Mean age (61.6 years), MSI-H frequency (3.8%), and mean bTMB (14.2 Mut/Mb) of KRAS G12D group is comparable to those of KRAS ND group. This contrasts with KRAS G12C with significantly lower mean age (60.2 years, p=0.01), lower MSI-H frequency (0.56%, p=0.03), and higher mean bTMB (16.3 Mut/Mb, p=0.02) compared to KRAS ND. Both KRAS G12D and G12C significantly co-occur with APC, PIK3CA, and SMAD4 alterations. FBXW7, AR, and KEAP1 alterations were unique co-occurrences to KRAS G12D, while KIT was unique to KRAS G12C. Candidate alterations associated with primary resistance in KRAS G12D CRC included simultaneously present mutations of KRAS Q61H (14.1%), G12V (6.4%), G12C (5.9%), G13D (3.6%), BRAF V600E (2.7%) and others, amplification of MET (2%), MYC (1.6%), and KRAS (1.4%), and FGFR3-TACC3 translocation (Table). Conclusions: KRAS G12D is associated with unique co-occurring molecular alterations compared to KRAS G12C in CRC. ctDNA-based NGS platforms can survey candidate alterations associated with primary resistance to KRAS G12D targeting in CRC. Further validation in preclinical models is needed. [Table: see text]
Association of KRAS G12C status with age at onset of metastatic colorectal cancer in the Brazilian population: A multicenter analysis of a molecular profile database (RAS, BRAF and MSI status).
Authors: Aruquipa Marcelo , Peixoto Renata D'Alpino , Dienstmann Rodrigo , Oliveira Fernanda , Lorandi Vinicius 
Published: January 2024

173 Background: Precision oncology has changed clinical practice in metastatic colorectal cancer (mCRC). However, there is little data about molecular epidemiology of mCRC in Brazil. Our study aims to create a nation-wide database to develop future projects in the Oncoclinicas Group. Methods: This was an observational, retrospective, and multicenter study. Anonymized medical records of adult patients (18 years or older) with mCRC from January 2019 to July 2023 were reviewed. All specimens were centrally reviewed in our laboratory (all tissue-based analysis). Demographic data included age, gender, region of origin and sidedness. Molecular data included RAS, BRAF and MMR status. Descriptive statistics, frequencies and percentages were used for categorical variables, while mean and medians for numerical variables. The correlation between variables was analyzed through Chi-square and T-test (when applicable). Significance for all results was established as a p value of < 0.05. The statistical software used was SPSS. Results: A total of 858 cases were included. Median age was 63.7 y/o (range 22-95) and 11.9% were < 45 y/o. Male patients represented 50.3% of the population and 76.1% were from the Southeast region. Left-sided tumors comprised 59.2% of the cases, 36.8% were right-sided and 4% were not specified. Wild-type KRAS corresponded to 46.7% of the total cases, while 49.4% were KRAS mutant and 3.9% NRAS mutant. The most common KRAS mutations were G12V (27.6%) and G12D (23.5%). KRAS G12C mutation was found in 6.4% of all KRAS mutant tumors. The most common NRAS mutation was the Q61K (24.2%). Only 7.3% of cases were BRAF mutated, most of them V600E, only 5 non-V600E mutations were detected. MSI-high was present in 14 cases only (1.6%). In the age-stratified analysis, left-sidedness (p=0.001) and KRAS G12C mutation (p=0.016) were associated with younger age (<45 y/o). In the sidedness-stratified analysis, younger age (p=0.001), BRAF mutation (p=0.001) and MSI-high status (p=0.009), were more common in right-sided tumors. Conclusions: In our Brazilian cohort of mCRC patients, frequencies of RAS and BRAF mutations were similar to worldwide data. However, we found lower than expected frequency of MSI-high tumors. KRAS G12C mutation was associated with early-onset mCRC, an emergent population in which KRAS G12C inhibitors might be particulary useful. To the best of our knowledge, this is the largest cohort in the Brazilian population with mCRC reporting RAS, BRAF and MSI status. Larger studies are needed to confirm these findings.
Impact of acquired RAS, BRAF and PIK3CA mutation at 8 weeks on the efficacy of anti-EGFR monoclonal antibodies in metastatic colorectal cancer.
Authors: Yamada Takeshi , Kataoka Kozo , Mori Keita , Kudo Toshihiro , Shiozawa Manabu , Takase Naoto , Ito Kazuma , Kimura Kei , Song Jihyung , Matsuhashi Nobuhisa , Miyasaka Toshimitsu , Tajima Jesse Yu , Beppu Naohito , Eda Hirotsugu , Oi Yuka , Yamazaki Kentaro , Ikeda Masataka 
Published: January 2024

193 Background: Recent studies indicate that the emergence of RAS/BRAF mutation sometimes occurs during initial anti-EGFR monoclonal antibody (mAb)-based treatment in metastatic colorectal cancer (mCRC). However, limited data was available regarding the timing and frequency of the emergence of RAS/BRAF mutation, and its impact on the efficacy of anti-EGFR mAb. With this background, we conducted an observational study to monitor RAS, BRAF, and PIK3CA mutation status by ctDNA in RAS/BRAF wt mCRC. Methods: RAS-trace is a pilot study to monitor RAS, BRAF, and PIK3CA mutation status by ctDNA, using NGS-based Plasma-Safe-SeqS technology for RAS/BRAF wt (diagnosed from tissue samples) mCRC treated with anti-EGFR mAb as a first-line chemotherapy. ctDNA- RAS/BRAF/PIK3CA status evaluated at baseline, 8, 12, 16, 20, 24, 36, 48 weeks and disease progression. The primary endpoint was the time to the acquired RAS mutations. The results of ctDNA at baseline and 8 weeks are presented. Results: Forty-two patients were enrolled, and 40 and 39 were used in the analysis of ctDNA at baseline and 8 weeks, respectively. All patients received mFOLFOX6 plus cetuximab (N=32) or panitumumab (N=8). At baseline, RAS, BRAF, and PIK3CA mutations were detected in 3, 3, and 1 of the 40 patients, respectively. One patient had both KRAS and BRAF mutations. Baseline ctDNA mutations were not associated with the presence of liver metastases, tumor sidedness, early tumor shrinkage, depth of response or skin rash ≥Grade 2. At 8 weeks, RAS, BRAF, and PIK3CA mutations were detected in 3, 2, and 0 among the 39 patients, respectively. One patient had both KRAS and BRAF mutations. ctDNA mutations at 8 weeks were not associated with the presence of liver metastases, tumor sidedness, or early tumor shrinkage, however, they were associated with depth of response and had a tendency of skin rashes ≥ Grade 2 (Table). Conclusions: Emergence of RAS/BRAF/PIK3CA mutations at 8 weeks may be related to the response of anti-EGFR mAb. The association of ctDNA status with survival outcomes will be presented in 2025. Clinical trial information: jRCT1050210160 . [Table: see text]