bluuebunny/crossref_metadata_2025 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]
Utilizing quantitative pathologic analysis of digitized images of rectal cancer (RC) to predict response to neoadjuvant therapy (NAT).
Authors: Walden Daniel , Eslinger Cody , Emiloju Oluwadunni Eunice , Storandt Michael H. , Hagen Catherine E. , Pfeiffer Ashlyn , Sonbol Bassam Bassam , Ahn Daniel H. , Bekaii-Saab Tanios S. , Ness Andrew , Wu Christina , Pai Reetesh , Ou Fang-Shu , Pai Rish , Hubbard Joleen M.
Published: January 2024

200

Background: We developed and validated a quantitative segmentation algorithm (QuantCRC) to predict disease recurrence in stage I-III colorectal cancer patients (pts) based on the analysis of digitized hematoxylin and eosin (H+E) stained pathology slides. In this study, we aim to determine if QuantCRC analysis on pre-treated RC biopsies can predict pathological complete response (pCR) after NAT which include total neoadjuvant therapy (TNT), chemoradiation (CRT) and others. Methods: Stage II-IV RC pts treated with curative intent modalities between 2005-2023 at Mayo Clinic and University of Pittsburgh were evaluated. Eligible pts had pre and post-treatment tissue available for analysis. Clinical characteristics, treatment, and outcome data were extracted from the medical record. QuantCRC extracted 15 features: %tumor, %stroma, tumor:stroma ratio, %TB/PDC, %mucin, %necrosis, %high-grade, %signet ring cells, tumor-infiltrating lymphocytes (TILs) per cm2 of a tumor, %immature stroma (tumor bed), %inflammatory stroma (tumor bed), %mature stroma (tumor bed), %immature (stromal region), %inflammatory (stromal region), and %mature (stromal region). The associations between the QuantCRC features and pCR were evaluated using Wilcoxon rank-sum tests and logistic regression models while adjusting for primary tumor location and NAT. Results: The identified 288 pts had the following demographics: median age 60, 59% male, 52% distal tumor, 42% TNT. Pts who achieved pCR had smaller pre-treatment tumors (p=0.03), higher TILS, and lower %immature (stroma) (Table 1). After multivariable adjustment, higher TILS and lower %immature (stroma) remain to be significantly associated with a higher likelihood of pCR. A higher %mature (stroma) and %mature stroma (tumor bed) were also identified, in multivariable models, to be associated with a higher rate of pCR. NAT protocol and tumor location (proximal vs. distal) were not associated with pCR. Conclusions: The ability to integrate pathological features with AI may allow for personalized treatment. Using this technology, we recognize that patients who harbor a more mature stromal archetype and inflammatory tumor predisposition, are more likely to achieve pCR to conventional NAT. These pathological features are not currently incorporated into risk stratification in RC. Additional validation and integration into current risk stratification methods is warranted. [Table: see text]
Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer using a multi-marker panel and a machine-learning approach: Final results of the prospective multicenter PERMAD trial.
Authors: Kestler Hans A. , Ettrich Thomas Jens , Stein Alexander , Arnold Dirk , Prager Gerald W. , Kasper Stefan , Niedermeier Michael , Müller Lothar , Kubicka Stefan , Koenig Alexander , Buechner-Steudel Petra , Berger Andreas , Wille Kai , Kestler Angelika , Kraus Johann M. , Werle Silke , Perkhofer Lukas , Lausser Ludwig , Seufferlein Thomas
Published: January 2024

204

Background: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. Methods: 15 German and Austrian centers prospectively recruited 154 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). Results: Using random forest machine learning, we developed a predictive model that discriminated between the situations of ”no progress within 100 days before radiological progress” and ”progress within 100 days before radiological progress”. Into this we incorporated a combination of ten out of the 102 CAF markers, which fulfilled this task with 81% accuracy, 72% sensitivity, and 88% specificity. Conclusions: Using artificial intelligence we identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress. Further studies are required to show its clinical value. Clinical trial information: NCT02331927 .
Association of pathologic nodal status with minimal residual disease after neoadjuvant treatment and resection of locally advanced rectal cancer.
Authors: Uppal Abhineet , Bhutiani Neal , Shen John Paul Y.C. , Alfaro Kristin , Kell Robert J. , Yousef Mahmoud M.G. , Yousef Abdelrahman M.G. , Konishi Tsuyoshi , Holliday Emma , Morris Van K. , Dasari Arvind , Willis Jason , Newhook Timothy E. , Bednarski Brian K. , You Y. Nancy , Peacock Oliver , Messick Craig , Das Prajnan , Chang George J. , Kopetz Scott
Published: January 2024

205

Background: Studies have shown that minimal residual disease (MRD) identified by detection of circulating tumor DNA (ctDNA) is associated with recurrence after surgical resection of colorectal cancer. Though multiple trials are evaluating the use of ctDNA to guide adjuvant therapy, data on the utility of ctDNA after neoadjuvant therapy is limited. In this study, we evaluated the associations between ctDNA and recurrence after neoadjuvant treatment and resection of rectal cancer (LARC). Methods: Consecutive patients with primary rectal cancer treated with neoadjuvant systemic therapy and/or chemoradiotherapy followed by resection between 12/2020-4/2023 were identified. Patients were tested for ctDNA via the MD Anderson INTERCEPT platform using a high-sensitivity patient informed assay. Patients with metastases or a first ctDNA test more than 3 months after resection were excluded. MRI-determined stage, extramural vascular invasion (mrEMVI), pelvic sidewall adenopathy (PSW), pathologic lymphovascular invasion (LVI), perineural invasion (PNI) and tumor regression grade (TRG) were collected. Associations between these factors and ctDNA status were analyzed with Fischer’s exact test. Recurrence free survival (RFS) was analyzed with the log-rank test. Results: Sixty-seven patients (3 treated with chemoradiotherapy alone, 15 with systemic therapy alone and 49 with total neoadjuvant therapy) were identified. Positive ctDNA was identified in 6 (8.9%) within 3 months after resection, all of whom received total neoadjuvant therapy, and 3/6 recurred within 12 months. Clinical T status (p=0.146), N status (p=0.842), mrEMVI (p=0.475) and PSW (p=0.318) were not associated with MRD. TRG was not associated with MRD (TRG0-1: 4% vs TRG2-3: 11.3%, p=0.547). Pathologic N status was associated with MRD (ypN0: 4.4% vs ypN+: 18%, p=0.049). MRD was associated with a median RFS of 3.2 months (HR 39, 95% CI: 4.1-380, p=0.0015). 1-year RFS was 98% for patients without MRD. Conclusions: Minimal residual disease after multi-modality treatment of LARC is associated with early metastatic recurrence. The patient informed MRD assay appears both sensitive and specific for detection of relapse. Advanced clinical stage and high-risk radiologic features were not associated with MRD, while post-treatment pathologic N status was. Given the high relapse rate for MRD+ patients, MRD detection after resection warrants additional investigation for metastases and/or enrollment on MRD treatment clinical trial. Methods to predict MRD prior to resection are urgently needed.
Identification of somatic alterations associated with brain metastases from a colorectal origin.
Authors: Strong James S. , Drebin Harrison M. , Walch Henry S. , Gui Chengcheng , Pike Luke Roy George , Moss Nelson S. , Sanchez-Vega Francisco , Smith Jesse Joshua
Published: January 2024

210

Background: Colorectal brain metastases (cBM) confer a devastating prognosis with survival of less than 13 months. Identifying genomic signatures to predict and guide treatment for these patients would be a valuable adjunct. This study evaluated genomic and clinicopathological features specific to cBM. Methods: cBM patients from the MSK-MET cohort were evaluated in comparison to other colorectal cancer patients with extracranial metastases (cOM). Clinicopathologic features and genomic alterations were analyzed with MSK-IMPACT, a targeted DNA sequencing panel for solid tumors and matched blood specimens. We considered mutations, copy number alterations, and fusions. Analyses of genomic features were restricted to microsatellite stable (MSS) patients. q-values were computed using Benjamini-Hochberg correction to account for multiple hypothesis testing. Patient record review identified patients with sequenced matched samples from the primary colorectal tumor and the brain metastases, which were then examined for loss and gain of assessed genetic alterations. Results: Of 130 patients with cBM identified from the cohort, 20 samples were from brain metastases, 52 from the primary CRC, and 58 from other metastatic sites. Average time to diagnosis of cBM was 3.5 years after primary colorectal cancer diagnosis and average time to death was 10 months after cBM diagnosis. Compared to the 3,383 cOM patients, cBM patients had significantly higher rates of both MSS CRC primaries (p<0.001, 122/130 cBM were MSS vs. 3,038/3,382 cOM) and primaries that originated in the rectum (p<0.002, with 38/130 cBM primaries from the rectum vs. 695/3,382 cOM rectal primaries). Somatic alterations in the KRAS, BRCA2, CDK8 and ERCC5 genes were significantly more frequent in patients with cBM compared to cOM patients (all p<0.001) (Table 1). Of the 9 patients who had matched primary and metastatic brain tissue sequenced, KRAS alterations were shared between the primary and brain metastasis in 2/9, ERBB3 and ERCC5 in 2/9, p53 in 6/9, and APC in 6/9 patients. In addition, newly acquired private alterations found only in the brain metastasis samples of matched patients included PIK3RI, ARID5B, NOTCH4, CYLD and SMAD4. Conclusions: We identify new genomic and clinical factors in cBM patients, including somatic alterations in potentially clinically actionable targets. To further explore potential clinical utility, these findings require validation in an independent cBM clinicogenomic dataset.[Table: see text]
Correlation of exploration of immune profile and genomic with microsatellite stable/tumor mutational burden-low colorectal cancer.
Authors: Abushukair Hassan Mohammed , Saeed Azhar , Sahin Ibrahim Halil , Saeed Anwaar
Published: January 2024

213

Background: Microsatellite stable/tumor mutational burden-low (MSS/TMB-L) tumors, represent the majority of colorectal cancer (CRC) patients and derive limited benefit from immune checkpoint inhibitors (ICI). Given the vast heterogeneity of this population, some patients may be candidates for ICI. Herein, we study the tumor immune microenvironment (TIME) and genomic correlates associated with favorable immune response in MSS/ TMB-L CRC patients. Methods: Using The Cancer Genomic Atlas Colorectal Adenocarcinoma (TCGA-COAD) cohort (n = 594), MSS patients (MSI Mantis score < 0.4) with TMB-L (<10 mutations/megabase) were identified. The CIBERSORT algorithm was used to calculate the fraction of 22 immune cells using RNA-seq data. Relevant immune expression signatures from the CRI iAtlas were used to assess TIME profiles. An antitumor immune activity (AIA) score was constructed using CD8+ T cells, T regulatory cells, and M1 & M2 macrophage fractions. Enriched mutations in MSS/ TMB-L patients with favorable antitumor immune scores were identified and used to stratify patients into favorable and unfavorable immune profiles (FIP & UIP). Comparisons were made using the Mann-Whitney U T-test and Fisher’s exact test. Results: We identified 430 (72.4%) MSS/TMB-L patients among the TCGA-COAD cohort. The AIA score ranged from – 0.44 to 0.62 (higher scores denote favorable AIA activity). The majority of patients (77%) had scores < 0. Top enriched mutated genes associated with higher scores included HMX2, BBS12, IFNLR1, SLC30A2, WDR48, ZNF329, H4C11, PARD3B, ENAM, ASCC1, CCDC88B, CMKLR1, IL21, KLHL11, and OTOP2. Patients harboring a mutation in one or more of these 15 genes were categorized in the FIP group (n=50, 11.6%) and patients with no mutations were categorized in the UIP group (n=360, 88.4%). The FIP group had significantly (p < 0.05) higher levels of TMB, CD8+ T cells, activated NK cells, M1 macrophages, immunogenic SNV mutations, and cytotoxic activity while patients with UIP had higher levels (p < 0.05) of M2 macrophages, neutrophils, and a trend for higher regulatory T cells and TH17 cells. Gene set enrichment analysis showed upregulation of T cell proliferation, interferon signaling, and Fanconi anemia pathway in FIP. Compared to UIP, FIP patients had a trend for better disease-specific survival after adjustment for CC subtype (colon vs. rectum) and age (HR: 0.26, 95% CI: 0.06-1.09, p = 0.066). Conclusions: Findings from this analysis highlight a subset of MSS/TMB-L CRC patients, with features of favorable anti-tumor immune response and unique mutation profile, that might derive benefit from immunotherapy. Further investigation is underway to further explore the genomic correlates in this subset of patients.
Impact of somatic genomic alterations in patients with metastatic colorectal cancer in a minority-rich academic medical center.
Authors: Jang Jessica , Khanimov Moisey , Johnson Devin , Zhang Chenxin , Moon Jee-Young , Bernabe Carolina , Kuang Chaoyuan
Published: January 2024

215

Background: Genomic alterations in metastatic colorectal cancer (mCRC) play a pivotal role in the clinical manifestations of the disease. Mutations have been associated with the age of onset of mCRC, tumor location, and metastatic sites. We conducted a retrospective study to explore the relationship between the genomic profile and clinical phenotype in a distinct patient population predominantly comprised of Hispanic and Black patients with mCRC. Methods: Patients with mCRC with available next-generation sequencing (NGS) treated at Montefiore Einstein Comprehensive Cancer Center (MECCC) who were diagnosed from January 2000 - January 2023 were included. Molecular testing was collected from: Perthera, Guardant, Caris, and Foundation One. The following parameters were collected: race, ethnicity, age of CRC diagnosis, age of metastatic diagnosis, metastatic sites, NGS profile, tumor location, and lines of treatment. Mutations were categorized into one of eight distinct pathways: cell cycle, MAP Kinase, WNT, homologous recombination, DNA damage repair, epigenetic modifications, transcription, & cell death. The primary endpoint was to examine the relationship between individual genetic alterations or any of these eight pathways and the clinical parameters. Results: 169 patients with microsatellite stable (MSS) mCRC were included (median age at diagnosis 59 years, 42% Hispanic, 38% Black). 148 distinct genetic alterations were discovered across our population, of which roughly half fit into one of eight clinical pathways. In concordance with previously published data, we found a significant association between PTEN and right-sided tumors (38% mutated in right-sided vs. 16% mutated in left-sided, p<.001). Cell cycle pathway mutations and SMAD4 mutations were associated with an earlier age of both primary CRC (p=.001 & p=.042, respectively) and metastatic diagnosis (p=<.001 & p=.013, respectively). CDK8 mutations were associated with atypical sites of metastases (p=.045). Conclusions: This analysis sought to deepen the understanding of how genomic alterations impacted the clinical phenotype in our population of mCRC patients. We identified previously undescribed associations between mutations in the cell cycle pathway and SMAD4 versus age of CRC diagnosis. As molecular sequencing in CRC continues to advance, these relationships may be further elucidated, which can potentially help guide treatment and identify higher-risk patients.
“Choosing wisely” in oncology: The example of surveillance positron emission tomography-computed tomography (PET-CT) for patients with colorectal cancer (CRC) treated with curative intent.
Authors: Tschernichovsky Roi , Razi Talish , Philosoph Keren , Menashe Idan , Arbel Ronen , Netzer Doron , Goldstein Daniel A
Published: January 2024

216

Background: Healthcare overuse is a major challenge for healthcare systems. Professional guidelines, such as “Choosing Wisely”, have been put in place to mitigate specific areas of overuse. We examined whether the rate of unwarranted PET-CT in CRC patients treated with curative intent was successfully reduced following the adoption of “Choosing Wisely". Methods: We used the large Clalit Health Services dataset in Israel to identify patients with CRC who received adjuvant chemotherapy for localized disease between January 2017-December 2021. We then examined the number of PETCTs performed for each patient. Results: 1799 patients were included in our study (Table). We distinguished localized from metastatic cases based on specific drugs administered or not administered during the follow-up period (i.e. biologics). For the entire cohort, the median number of PETCTs performed per patient over the study period was 3. 364 (20.2%) patients underwent a single PETCT, 946 (52.6%) patients underwent ≥2 PETCTs, and 25 patients underwent ≥ 10 PETCTs. Assuming a single PETCT is considered “guideline concordant” during diagnosis and treatment of localized CRC, 52.6% (946/1799) of patients in our cohort underwent “guideline discordant” PETCT scans. Conclusions: Despite professional guidelines recommending against routine PETCT to monitor for recurrence following curative-intent treatment of CRC, there remains a large volume of “guideline-discordant” PETCTs in this space. Professional guidelines such as “Choosing Wisely” have largely failed to prevent this example of healthcare overuse. [Table: see text]
The power of glycobiology: Precision of polyp detection using glycoproteomic biomarkers.
Authors: Chandrasekar Dharini , Ding Nik Sheng , Wallace Michael B. , Norez Daniel , Guerrier Christina , Ramachandran Prasanna , Caval Tomislav , Desai Khushbu , Xu Gege , Serie Daniel , Hommes Daniel
Published: January 2024

22

Background: Glycosylation plays a pivotal role in host immune response during cancer development. Recently, we have reported specific changes in blood-based glycoforms for the early detection of advanced adenomas (AAs) and colorectal cancer (CRC). This study aims to identify glycoproteomic biomarkers associated with various polyp types, as glycosylation abnormalities are linked to neoplastic transformation, and CRC risk varies by polyp histology. Methods: Samples from an observational study (NCT05445570) were used to identify three distinct histologic polyp groups: adenomatous (AP), hyperplastic (HP), or serrated (SP). Combining liquid-chromatography/mass-spectrometry and artificial-intelligence powered data processing, our glycoproteomic profiling platform assessed glycopeptide (GP) and non-glycosylated peptide quantification transitions from the serum samples. We used multi-nominal response logit models to examine the relationship between polyp types and biomarkers. An a priori biomarker panel was interjected as exposures in the model. Each marker is assessed independently for inclusion into our final model. The final model utilized biomarkers found to have a significant association with the presence of AP, SP, or HPs along with age, sex, and BMI. Results: We identified 1,035 subjects with distinct polyp histologies and 1,300 polyp-free controls. We found a significant increase in relative risk (RR) for polyp presence in patients who were: >60 years (AP RR 1.40), male (AP RR 1.74), or had a BMI> 25. From the GP biomarker panel, 15 GPs were associated with risk of polyp presence; however, only 7 GP markers were significantly associated after adjusting for age, sex, and BMI. Two biomarkers were found to have a protective effect for the risk of an adenomatous polyp (RR 0.37; RR 0.39). Three biomarkers increased the risk of an adenomatous polyp (RR 1.31; RR 1.42; RR 1.98). One biomarker was found to increase the risk of a hyperplastic polyp (RR 1.42). Two biomarkers were found to increase the risk of serrated polyps (RR 1.67; RR 2.08) and one biomarker was found to decrease the risk of serrated polyps (RR 0.77). Conclusions: This is a novel exploratory study using GP biomarkers as it relates to risk of polyp presence by distinct histology. The use of these biomarkers allows us to harness the power of glycobiology in the liquid biopsy domain for AAs/CRC detection. The exact function of these GP markers during the development of different polyp types needs to be further explored through future studies.
Comparison of palliative treatment modalities among patients with colon cancer: A review of NCDB Database.
Authors: Jafry Baqir , Buhaya Munir , Kazmi Syed Mohammad Ali
Published: January 2024

220

Background: Among colon cancer patients some patients present with significant symptom burden needing upfront palliation-directed therapies, aimed to improve the quality of life of patients with severe illnesses. These include palliation-directed surgery, chemotherapy, radiation, pain management, or a combination of these. The extent to which these palliation-directed therapies are utilized in colon cancer remains under-explored. This study's purpose was to understand the trends in utilization and factors associated with palliation-directed treatment modalities among patients with colon cancer. Methods: From the National Cancer Database, we identified patients with colon cancer who received first-line palliation-directed therapies from 2004 to 2016 without an intent to give definitive therapy. We evaluated the use of these treatments over time and compared frequencies of categorical variables using Chi square tests. A multivariate logistic regression was also used to evaluate patient characteristics associated with the use of these treatments. Results: We identified a total of 21,516 patients receiving palliation-directed therapy among patients with colon cancer – 19,506 received single palliation-directed therapy, 908 received a combination of palliation-directed treatments without pain management and 1102 received a combination of palliation-directed treatments with pain management. Of the 21,516 patients who received single palliation-directed treatments, 50.6% and 49.4% were male and female, respectively. The mean age was 67 years. Most patients had no existing comorbidities (68.7%), lived in metropolitan areas (81.6%), had grade 2 (59.4%) and AJCC Clinical stage 4 colon cancer (32.6%). Overall, most patients received chemotherapy (50.7%) as a palliative treatment, followed by surgery (25.2%), pain management (14.4%) and radiation (9.7%). The utilization of chemotherapy (39.6% in 2004 to 63.1% in 2016) and pain management (9.7% in 2004 to 12.7% in 2016) increased over time while the utilization of surgery (37.1% in 2004 to 16.9% in 2016), and radiation (13.6% in 2004 to 7.3% in 2016) decreased over time. The type of facility, readmission rates, and proportion of individuals who were whites, elder (age>50), resided in metropolitan areas and had insurance were significantly different between groups. Male patients, patients without existing comorbidities, and patients with grade 2 tumors had higher odds of receiving surgery, radiation, or chemotherapy as palliative therapy compared to pain management. Conclusions: Utilization of first-line palliation-directed chemotherapy has increased significantly from 2004 to 2016 whereas surgery and radiation therapy use has decreased in that period. Notably, patient characteristics such as gender, absence of existing comorbidities and grade 2 tumors influence the choice of therapy.