Browse Articles
Discover research articles across all indexed journals
Prognostic impact of postoperative complications after neoadjuvant therapy followed by esophagectomy for esophageal cancer: An exploratory analysis of phase III trial JCOG1109.
356 Background: We previously reported that postoperative complications after esophagectomy were significantly associated with poor long-term prognosis in the prospective randomized trial JCOG9907 (Ann Surg, 2017). JCOG1109 evaluated the efficacy and safety of neoadjuvant docetaxel plus cisplatin plus 5-FU (DCF), radiation with cisplatin plus 5-fluorouracil (CF-RT) compared with cisplatin plus 5-fluorouracil (CF) for locally advanced esophageal squamous cell carcinoma, and demonstrated the superiority of DCF compared with CF in improving overall survival (OS). In this exploratory analysis, we investigated the association between postoperative complications and prognosis in JCOG1109, where more intensive preoperative therapies and thoracoscopic esophagectomy (TE) were introduced. Methods: Patients with potentially resectable advanced thoracic esophageal cancer were randomly assigned to CF, DCF, or CF-RT therapies and followed by open esophagectomy (OE) or TE with regional lymphadenectomy in JCOG1109. The impacts of postoperative complications (≥ Grade 2) on long-term prognosis including OS and progression-free survival (PFS) were investigated in each of the three preoperative therapies. Results: Between December 2012 and July 2018, 601 patients were randomized (CF/DCF/CF-RT; 199/202/200). Of 589 eligible patients, 541 patients underwent esophagectomy (183/181/177). Any postoperative complications, pneumonia, anastomotic leakage, recurrent laryngeal nerve paralysis, or infectious complications had no significant impact on OS in each of the three arms. When divided into OE or TE, the impact of any postoperative complications on OS was attenuated by introducing TE in each of three arms; from neoadjuvant CF followed by OE group [hazard ratio (HR) 1.557, 95% confidence interval (CI) 0.881-2.752] to TE group [HR 0.802, 95% CI 0.424-1.515], from neoadjuvant DCF followed by OE group [HR 1.151, 95% CI 0.575-2.306] to TE group [HR 0.703, 95% CI 0.3363-1.471], and from neoadjuvant CF-RT followed by OE group [HR 1.548, 95% CI 0.840-2.852] to TE group [HR 1.186, 95% CI 0.627-2.245]. Conclusions: JCOG1109 showed no association between postoperative complications and long-term prognosis. The prognostic impact of postoperative complications might be attenuated by the introduction of minimally invasive esophagectomy (open to thoracoscopy) even after more intensified preoperative therapy (CF to DCF or CF to CF-RT). Clinical trial information: CRB3180009.
Metalloparticle‐Engineered Pickering Emulsion Displaying AAV‐Vectored Vaccine for Enhancing Antigen Expression and Immunogenicity Against Pathogens
AbstractRecombinant adeno‐associated viruses (rAAVs) have emerged as promising vaccine vectors due to their enduring efficacy with a single dose. However, insufficient cellular immune responses and the random and non‐specific distribution of AAVs post‐injection may hinder the development of AAV vaccines. Here, a novel Pickering emulsion platform stabilized by biomineralized manganese nanoparticles and aluminum hydroxide, which can rapidly and efficiently load AAVs, is reported. This platform confers AAVs with favorable in vivo distribution kinetics, diversifying AAV endocytic pathways with reduced dependency on the sialic acid receptor‐mediated route, and ultimately enhancing AAV infection efficiency in antigen present cells (APCs). Concurrently, the Pickering emulsion substantially boosts endogenous 2′3′‐cGAMP production, further activating the cGAS‐STING pathway for stronger immune responses and improving protective efficacy in bacterial infection models. The STING pathway activation also increases AAV target gene expression, potently augmenting the cross‐protective potential of AAV vaccines for COVID‐19. These synergistic effects ensure that effective immune responses are induced even at one‐fifth of the AAV vaccination dose, while the Pickering emulsion further reduces the accumulation of AAV in the liver, thereby improving their safety. The findings highlight the potential of Pickering emulsions as valuable enhancers for viral vectors, providing insights for their broader clinical applicability.
Mortality trends and racial disparities in hepatocellular carcinoma associated with metabolic syndrome in the United States and Texas: A 21-year analysis (1999-2020) using CDC WONDER database.
525 Background: The prevalence of hepatocellular carcinoma(HCC) and metabolic syndrome (MetS) is increasing globally. This study aims to examine annual trends of mortality in MetS-associated HCC in the United States and its state of Texas, from 1999 to 2020, to evaluate public health initiatives and identify socioeconomic factors. Methods: Mortality trends for adults aged ≥25 years with MetS-associated HCC were analyzed using CDC WONDER database, identifying deaths through ICD-10 codes C22.9 “Liver Malignant neoplasms” and E88.9 “Metabolic Syndrome”. Crude and age-adjusted mortality rates (AAMRs) per 100,000 people were extracted. Annual percent changes (APCs) in AAMRs, with 95% confidence intervals, were determined across various demographic (sex, race/ethnicity, age) and geographic (state, urban-rural, regional) subgroups. Results: Between 1999 and 2020, 271,046 documented deaths were attributed to HCC due to metabolic syndrome. The AAMR for MetS-related HCC mortality increased in the US from an adjusted rate (AR) (3.7) in 1999 to (4.5) in 2009 (APC:2.10%; 95% CI: -0.13% to 3.10%), after which it increased to (7.6) in 2018 (APC:5.83%; 95% CI:4.25% to 6.99%) and increased to 9.9 in 2020 (APC:13.19%; 95% CI:8.78% to 15.7%). In Texas, AAMR for MetS-related HCC mortality increased from AR (4.9) in 1999 to (8.9) in 2015 (APC:3.95%; 95% CI:3.11% to 4.69%) after which it increased to (15.3) in 2020 (APC:10.64%; 95% CI:8.18% to 17.33%). Men had consistently higher AAMRs than women (12.4 vs. 8). The AAMR in U.S. men increased from (5.1) in 1999 to (12.4) in 2020. The AAMR in U.S. women increased from (2.7) in 1999 to (8) in 2020. The non-Hispanic (NH) American Indian or Alaska Native population has the greatest AAMR (13.4), followed by the NH Black or African American(AA) (12.7) and the Hispanic or Latino population with AAMR (10.9). The low-risk population was NH White with AAMR (9.6) and NH Asian or Pacific Islander (6.6). The AAMR also varied by region (South:11.5; Midwest:9.9; West:9.4; Northeast:7.4) and non-metropolitan areas had higher AAMR (small metro:12.1; non-core areas:11; micropolitan areas:11.7) than metropolitan areas (large central metropolitan: 8.8; large fringe areas: 8.7). The states in the upper 90th percentile of MetS-related HCC AAMRs were Texas, Louisiana, Arkansas, Michigan, Nevada exhibited an approximately two-fold increase in AAMRs, compared to states falling in the lower 10th percentile Nebraska, Wisconsin, Washington, Maine. Conclusions: Mortality rates from hepatocellular carcinoma associated with metabolic syndrome have risen in the United States and Texas over the past two decades. However, significant demographic and geographic disparities in MetS-related HCC mortality continue, emphasizing the need for further investigation and the development of targeted treatment strategies.
A study of the homologous recombination deficiency signature (HRDSig) status of advanced esophageal squamous cell carcinoma (AESCC) by utilizing comprehensive genomic profiling (CGP).
485 Background: The role of poly-ADP-ribose polymerase (PARP) inhibitors is currently under investigation as a potential therapeutic option for AESCC. Homologous recombination deficiency signature status (HRDSig) positivity has been shown to predict biallelic loss of BRCA1/2 which may simultaneously portend a worse prognosis and a sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. In this study, we attempt to characterize the genomic alterations present in AESCC based on HRDSig status utilizing comprehensive genomic profiling (CGP) techniques. Methods: 2,029 cases of AESCC underwent comprehensive genomic profiling with an examination of all genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and genomic trinucleotide signatures were determined from the sequencing data. HRDSig status was calculated using a broad set of genome-wide copy number features (PMID 37769224). Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery. Results: 154 (7.6%) of the 2029 AESCC cases featured a positive HRDSig status (HRDSig+). The age (66-67) and gender (58%-63% male) distribution were similar in the HRDSig+ and HRDSig- AECSS cases as was the frequency of GA/tumor (9 for both). The median TMB was higher in the HRDSig+ (6.3 vs 3.8; P<.0001) as was frequency of TMB > 10 mutations/Mb (19.5% vs 10.0%; P=.004). An APOBEC trinucleotide signature was also more frequent in the HRDSig+ AESCC (11.0% vs 5.4%; P=.05). As anticipated, GA in genes associated with HRD including BRCA1 (10.4% vs 1.4%; P<.0001) and BRCA2 (14.3% vs 2.0%; P<.0001) was present. MTOR pathway activating mutations were also more frequent in the HRDSig+ AESCC group including PTEN (13.0% vs 7.3%; P=.06). Conclusions: With a 7.6% frequency, HRDSig+ status is a relatively rare event in AESCC. CGP with determination of HRDSig status in AESCC may prove useful in tailoring PARP inhibitor-based treatment regimens and may potentially uncover other genomic alterations that can aid in designing targeted therapy combinations in future. Characteristics of comprehensive genomic profiling of clinically advanced esophageal squamous cell carcinoma by HRDSig status. AESCC HRDSig- (n=1875) AESCC HRDSig+ (n=154) P-value Pathogenic genomic alterations BRCA1 1.4% (26) 10.4% (16) 0.00 BRCA2 2.0% (36) 14.3% (22) 0.00 PTEN 7.3% (137) 13.0% (20) 0.06 COSMIC trinucleotide signature APOBEC 5.4% (101) 11.0% (17) 0.05 Tumor mutational burden (TMB) Median TMB (range) (IQR) 3.8 (0-85) (2.5-6.3) 6.3 (0-61) (3.8-8.8) 0.00 TMB≥10 mut/Mb 10.0% (188) 19.5% (30) 0.00
Efficacy and safety of anlotinib as a later-line treatment for advanced colorectal cancer.
194 Background: Colorectal cancer (CRC) is increasingly prevalent in China, with rising incidence and mortality rates. Often, early-stage CRC presents with no symptoms, leading to most patients being diagnosed at an advanced stage, where prognosis is poor. First- and second-line treatments for advanced CRC typically include chemotherapy combined with cetuximab or bevacizumab. However, third-line therapies such as regorafenib, furosemide, and TAS102 have shown limited efficacy. Anlotinib, a multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated improved progression-free survival (PFS) in refractory metastatic CRC (mCRC) in a phase III trial (NCT02332499), showing both efficacy and manageable toxicity. This report provides updated results from extended follow-up. Methods: This study enrolled 73 patients with advanced colorectal cancer who had undergone at least two prior standard treatments and were treated with oral anlotinib hydrochloride (8-12 mg daily, days 1-14 of a 21-day cycle) between November 2021 and March 2024 at Tangdu Hospital. Patients were treated until disease progression or intolerable adverse events. Efficacy was assessed using RECIST version 1.1, and adverse reactions were evaluated using CTCAE version 5.0. The primary endpoints were PFS, disease control rate (DCR), and adverse events (AEs), while secondary endpoints included overall survival (OS). Results: Of the 73 patients included, 38 had an ECOG performance status (PS) of 0-1, and 35 had a PS of 2. Clinical staging identified 18 patients with stage IIIB/IIIC and 55 with stage IV disease. Patients received anlotinib doses of 8 mg (n=11), 10 mg (n=44), or 12 mg (n=18), with 48 patients also receiving chemotherapy and 25 receiving anlotinib alone. The median PFS was 4.0 months (95% CI: 3.4-4.6), and the median OS was 7.0 months (95% CI: 5.7-8.3). Subgroup analysis indicated that patients under 60 years of age, those without liver metastases, and those with ECOG PS 0-1 derived greater benefit from anlotinib. The most common treatment-related adverse event was hypertension (19.2%). Other notable adverse events included elevated AST (11.0%), proteinuria (6.8%), and jaundice (6.8%). Most adverse reactions were grade 1-2, although 1 patient experienced grade ≥3 gastrointestinal bleeding. Conclusions: Anlotinib showed promising efficacy and a favorable safety profile as a later-line treatment for advanced colorectal cancer. These findings suggest that anlotinib may be a viable clinical option for advanced CRC, though larger-scale clinical trials are necessary to confirm these results and further define its role in treatment.
Efficient Photocatalytic Propane Direct Dehydrogenation to Propylene Over PtO<sub>2</sub> Clusters
AbstractThe direct dehydrogenation of alkanes to olefins under mild conditions is challenging due to the inert nature of alkyl C─H bonds. Herein, an efficient photocatalytic system is developed for propane direct dehydrogenation (PDH) to propylene, consisting of ≈1.30 nm sized PtO2 clusters immobilized on a layered double hydroxide ‐derived ZnO/Al2O3 support (LD‐Ptn). Under UV excitation (365 nm), photogenerated holes in ZnO migrate to Pt sites at PtO2/ZnO interfaces, thereby activating and dissociating C─H bonds in propane. A propylene production rate of almost 1 mmol g−1 h−1 and a nearly 100% selectivity are achieved for the compositionally optimized LD‐Ptn photocatalyst. Control experiments and density functional theory calculations further verify that the excellent photocatalytic PDH performance of LD‐Ptn stems from synergism between ZnO semiconductor and the loaded Pt species. This work identifies a promising new route for direct production of olefins from alkanes.
Identifying the optimal post-surgical timing of molecular residual disease (MRD) detection in colorectal cancer (CRC) using an ultra-sensitive assay: Interim results from the VICTORI study.
275 Background: While detection of MRD using ctDNA is prognostic for recurrence in CRC, some patients still recur prior to MRD detection. VICTORI is prospectively investigating NeXT Personal, an ultra-sensitive NGS-based MRD assay, to profile patients with resected CRC. Methods: Patients with CRC treated with curative intent (all stages) are tested for MRD using NeXT Personal, a bespoke assay with up to ~1,800 tumor-informed single nucleotide variants (SNVs) identified from whole-genome sequencing. Plasma is collected prior to surgery, every 2 weeks post-surgery up to week 8 (MRD landmark window), and every 3 months for up to 3 years (surveillance). We present preliminary results on 397 samples from the first 62 patients. Results: A total of 62 patients (N=36 rectal [58%], N=26 colon [42%]; N=46 stage I-III [74%], N=16 stage IV [26%]) were included in our analysis. Baseline pre-surgical sensitivity (treatment naive) was 93.5% [N=29/31]. Pre-surgical positivity rate in patients who had received neoadjuvant therapy and had residual cancer at the time of surgery was 67% [N=16/24]. 60 patients were evaluable for clinical outcomes. At a median follow-up of 355 days, 15 patients (25%) had a recurrence. Of these, all patients were ctDNA-positive prior to recurrence (100%, 14/14; 1 pt excluded due to lack of samples prior to recurrence). ctDNA detection preceded clinical relapse by a median of 194 days [range: 5-397]); ctDNA for 78.6% (N=11/14) were first detected in the MRD landmark window. All landmark-positive recurrences occurred within one year of surgery. The 14 recurrent cancers with samples were first detected at a median ctDNA concentration of 28.7 parts per million (PPM) (range 2.4-111,120), with 64.3% (9/14) of those detections in the ultra-low range of <100 PPM. MRD detection at week 4 and week 8 had the greatest reduction in RFS (HR 12.86 [2.74-60.28], p=0.0012 week 4; HR 16.14 [3.52-74.09], p=0.0004 week 8), with weeks 4, 6 and 8 having similar higher prevalence of ctDNA detection (36.0% [18/50], 35.3% [18/51], 38.5% [20/52] respectively). Week 2 detection rate was 17.0% (8/46). cfDNA concentration was highest at week 2 (4.63ng/ml vs. 2.22 at baseline, p=0.00028) and 4 (3.68 vs. 2.22, p=0.0081), returning to baseline levels at week 6 (2.28 vs. 2.22, p=0.67) and 8 (2.48 vs. 2.22, p=0.64). Conclusions: In this interim report after a median ~1 year follow-up, NeXT Personal detected MRD for all patients prior to disease recurrence. Most initial MRD detection was in the ultra-sensitive range <100ppm and detection at 4-8 weeks after surgery was highly prognostic for recurrence.
Universal screening for mismatch repair deficiency in gastrointestinal cancers in a reference center in Mexico.
840 Background: Gastrointestinal (GI) cancers have a poor prognosis. With the availability of immunotherapy for tumors with deficient mismatch repair (dMMR), identifying these patients has become increasingly important. Universal dMMR screening across all GI cancers is uncommon, and its prevalence has not been well studied prospectively. In Mexico, the prevalence of dMMR is unknown, even though GI cancers account for a large portion of new cancer cases and cancer-related deaths. Our objective was to prospectively determine the prevalence of dMMR in GI cancers at a referral center in Mexico. Methods: Prospective universal screening for dMMR began in March 2024. Primary tumor sites included were esophagus, stomach, pancreas, biliary tract, small intestine, colon, and rectum. Histologies included were adenocarcinoma, squamous cell, or mixed. All consecutive patients were included regardless of age, clinical stage or medical history. MMR status was determined by immunohistochemistry, analyzing expression of MLH1, PMS2, MSH2, and MSH6. This abstract presents the results from the first six months of this universal screening. Results: A total of 161 GI cancers were included (see Table). Prevalence of dMMR was 9.3% (n=15). The highest prevalence was in gastric cancer (13.3%, 2/15), followed by colon (12.1%, 7/58), pancreatic (11.1%, 4/36), and bile duct (8.3%, 2/24) cancer. MMR status was not performed in 9.3% (n=15) of cases. Combined deficiency was found in 60% (9/15) for MLH1/PMS2 and 20% (3/15) for MSH2/MSH6. Isolated deficiency occurred in 20% (3/15) for PMS2 and 13.3% (2/15) for MSH2. No difference in age or clinical stage was observed between MMR status groups. Conclusions: The high prevalence of dMMR, along with the poor prognosis and availability of immunotherapy based treatments, supports the need for universal screening. The high prevalence of dMMR in pancreatobiliary cancers was notable. Implementation efforts in our institution are essential to obtain MMR status in all cases. Characteristics of population. pMMRn=131 (%) dMMRn=15 (%) Not performedn=15 (%) Totaln=161 p value Gender Male 63 (48.1) 10 (66.7) 7 (46.7) 80 (49.7) 0.38 Female 68 (51.9) 5 (33.3) 8 (53.3) 81 (50.3) Age Median (IQR) 65 (54 -72) 52 (43 -80) 65 (57 -71) 65 (53 -72) 0.52 Histology Adenocarcinoma 130 (99.2) 15 (100.0) 14 (93.3) 159 (98.8) N/A Mixed 1 (0.8) 0 (0.0) 0 (0.0) 1 (0.6) Squamous Cell 0 (0.0) 0 (0.0) 1 (6.7) 1 (0.6) Clinical Stage Unknown 12 (9.2) 1 (6.7) 1 (6.7) 14 (8.7) 0.49 Localized 24 (18.3) 2 (13.3) 2 (13.3) 28 (17.4) Locally advanced 40 (30.5) 8 (53.3) 3 (20.0) 51 (31.7) Metastatic 55 (42.0) 4 (26.7) 9 (60.0) 68 (42.2) Tumor site Esophageal 9 (6.9) 0 (0.0) 1 (6.7) 10 (6.2) N/A Gastric 13 (9.9) 2 (13.3) 0 (0.0) 15 (9.3) Small B. 1 (0.8) 0 (0.0) 0 (0.0) 1 (0.6) Bile duct 14 (10.7) 2 (13.3) 8 (53.3) 24 (14.9) Pancreas 29 (22.1) 4 (26.7) 3 (20.0) 36 (22.4) Colon 50 (38.2) 7 (46.7) 1 (6.7) 58 (36.0) Rectal 15 (11.5) 0 (0.0) 2 (13.3) 17 (10.6)
Frequency and impact of a genome-wide homologous recombination deficiency signature (HRDsig+) on the genomic landscape of advanced colorectal cancer (CRC).
238 Background: There have been significant advancements in novel therapies that target the DNA damage response pathway, and utilizing scar-based measures of homologous recombination deficiency (HRD) beyond genomic alterations (GA) in BRCA1/2 may provide opportunities for additional biomarker-driven therapies for patients with advanced CRC. Methods: We identified 47,028 cases of advanced CRC for comprehensive genomic profiling (CGP) to examine all classes of GA and measure HRDsig+ status. HRDsig status was calculated using a broad set of genome-wide copy number features (PMID 37769224) and was correlated with microsatellite status, tumor mutation burden (TMB), genomic ancestry, trinucleotide mutational signatures, and PD-L1 IHC using the Dako 22C3 tumor proportional score (TPS) system. Categorical variables were compared using the Fisher exact test with the Benjamini-Hochberg adjustment to correct for false discovery rate. Results: A total of 796 (1.7%) advanced CRC tumors were HRDsig+ with a median age of 62 years for HRDsig+ and 63 years for HRDsig-. The HRDsig- cohort was more likely to be male compared to HRDsig+ (56.1% vs 50.4%; P=.004). Median GA per tumor was similar (range 5-6) in both groups. Genomic ancestry revealed significantly more African ancestry in the HRDsig- group (12.6% vs 8.8%; P=.002) and more European ancestry in the HRDsig+ group (75.8% vs 71.6%; P=.02). MSI-high status was more frequent in HRDsig- group as compared to the HRDsig+ group (5.5% vs 1.6%; P<.0001). Median TMB was higher in the HRDsig+ cohort (5.0 vs 3.6; P<.0001), as was frequency of TMB ≥ 10 mutations/Mb (16.2% vs 8.5%; P<.0001). Trinucleotide mutational signature distribution was similar in both cohorts with the exception that a tobacco signature was more frequent in the HRDsig+ group (1.5% vs 0.2%; P<.0001). Both PD-L1 low (1-49% TPS) expression (19.5% vs 13.1%; P=.005) and PD-L1 high (≥50% TPS) expression (4.4% vs 1.5%, P=.0021) were higher in HRDsig+ cases. GA in genes associated with HRD were BRCA1 (13.6% vs 1.1%; P<.0001), BRCA2 (8.4% vs 2.8%; P<.0001), ATM (8.0% vs 5.3%; P=.0003), and RAD21 (6.7% vs 3.2%; P<.0001), which were more frequent in the HRDsig+ group. In the HRDsig- group, 83.7%/88.8% of BRCA1 / BRCA2 mutated CRC were not bi-allelic, likely non-driver GA. ERBB2 GA were similar in both groups (5.3% vs 4.4%; P=0.31). KRAS GA were more frequent in the HRDsig+ group (49.1% vs 31.7%; P<.0001). Conclusions: This analysis is the largest assessment of HRD status in advanced CRC. HRDsig+ was 1.7% and is associated with co-occurring actionable GA compared to HRDsig- tumors and higher levels of PD-L1 TPS, which may provide opportunities to target these tumors with immunostimulatory therapies. Given the advances in novel DNA repair targeted therapies these results may provide insight for CRC clinical development for DNA repair combinations.
Analysis of clinically actionable alterations in baseline tumor versus plasma samples in participants of the TOPAZ-1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer.
625 Background: In the TOPAZ-1 study (NCT03875235), durvalumab + gemcitabine and cisplatin (D+GC) significantly improved overall survival (OS) versus placebo + GC (P+GC) in participants (pts) with advanced biliary tract cancer. Updated results have shown a clinically meaningful long-term OS benefit for D+GC versus P+GC at 3 years. This exploratory analysis tested circulating tumor DNA (ctDNA) in plasma samples for blood-based detection of clinically actionable alterations (CAAs) and investigated the potential of this method to guide treatment decisions. Methods: Baseline genomic alterations were retrospectively assessed in evaluable tumor (FMI biomarker evaluable population [BEP], n=441) and plasma samples (GH BEP, n=643) using FoundationOne (Foundation Medicine Inc., Cambridge, MA) and Guardant INFINITY (Guardant Health, Redwood City, CA) assays, respectively. Mutation prevalence and association with outcomes were compared in the FMI BEP and GH BEP. Positive and negative percent agreement of CAAs detected in tumor versus ctDNA were assessed in 419 pts with both tumor and plasma samples (FMI-GH BEP). Results: The FMI BEP and GH BEP represented 64% and 94% of the TOPAZ-1 final analysis set (685 pts), respectively. The relative prevalence and overall mutational landscape detected in plasma ctDNA was consistent with that observed by tumor profiling, with the notable exception that genes harboring complex alterations (e.g. gene amplification, rearrangements, or homozygous deletions) were less frequently detected in ctDNA (e.g. ERBB2 , FGFR2 , and CKDN2A/2B/MTAP ). The most common alterations (>15% prevalence in both BEPs) observed were in TP53 (49%/52%), KRAS (24%/17%), and ARID1A (21%/16%) (in the FMI/GH BEPs, respectively). The relative prevalence of alterations within geographic and anatomic subgroups was similar in tumor versus plasma for most CAAs. The overall percent agreement in CAAs was ≥93%, and negative percent agreement was ≥97%. However, positive percent agreement was notably low for ERBB2 amplification (52%) and FGFR2 fusions (47%). OS hazard ratios for D+GC versus P+GC in the GH BEP were <1 for both CAAs and wild-type, except for ERBB2 amplification, as previously reported in the FMI BEP. Conclusions: The overall concordance and relative prevalence of simple mutations (e.g. single nucleotide variants) were similar using the FoundationOne tumor assay and Guardant INFINITY ctDNA assay, suggesting that plasma ctDNA testing has potential utility in clinical practice. However, negative status by ctDNA for the complex alterations found in FGFR2 and ERBB2 would require further testing of tumors, based on their low detectability in plasma. Clinical trial information: NCT03875235 .
Survival disparities in small intestine carcinoid tumors: A SEER-based analysis.
653 Background: Small intestine carcinoid tumors (SI-carcinoids) are rare neuroendocrine neoplasms with variable survival outcomes. This study examines the impact of age, sex, race, income, and geographic location on overall survival (OS) in patients with SI-carcinoid tumors. Methods: A retrospective cohort study was conducted using the Surveillance, Epidemiology, and End Results (SEER) registry 22 to identify patients aged 20 and above with SI-carcinoid tumors from 2000 to 2021. Kaplan-Meier survival analysis and log-rank tests were used to assess differences in survival. Cox proportional hazards models estimated hazard ratios (HR) for Overall Survival (OS). Results: 20,777 patients were included, with 7,029 deaths recorded. Median OS varied significantly by age, sex, race, income, and tumor site. Patients aged 60-85 had a median OS of 10 months (95% CI: 9.75-10.42), while those over 85 had 2.92 months (95% CI: 2.67-3.33). Females had better OS (13.92 months; 95% CI: 13.42-14.42) than males (12.83 months; 95% CI: 12.42-13.25). Non-Hispanic Black patients had worse OS (12.33 months; 95% CI: 11.50-13.33) compared to Non-Hispanic Whites (13.25 months; 95% CI: 12.92-13.67). Patients earning less than $50,000 had worse OS (11.42 months; 95% CI: 10.67-12.42) than those earning $100,000–$120,000 (15.42 months; 95% CI: 14.25-17.83). Geographic disparities were noted, with nonmetropolitan areas showing worse OS (11.42 months; 95% CI: 10.83-12.92) compared to large metropolitan areas (14.00 months; 95% CI: 13.50-14.42). Cox models confirmed age (HR for 85+ years: 21.99; 95% CI: 17.40-27.81), male sex (HR: 1.12; 95% CI: 1.07-1.17), and Black race (HR: 1.29; 95% CI: 1.18-1.42) were linked to worse OS. Tumor site also affected OS, with ileal tumors showing better survival compared to duodenal tumors (HR: 0.89; 95% CI: 0.84-0.94). Conclusions: Age, sex, race, income, and geographic location significantly affect OS in patients with small intestine carcinoid tumors, highlighting the need for tailored interventions for vulnerable groups.
Long-term outcomes of total neoadjuvant treatment (TNT) for locally advanced rectal cancer: Maria Sklodowska Curie National Cancer Research Institute (MSCNCRI) cohort from Polish-II study.
84 Background: The data on long-term outcomes of TNT for locally advanced rectal cancer are still limited. The Polish-II study randomized 515 cT4/fixed cT3 rectal cancer to pre-operative chemoradiation (CRT) with 5fu/oxaliplatin or 5x5 Gy radiotherapy with consolidating chemotherapy (TNT). Despite the early separation of survival curves with benefit for TNT, the outcomes at the longer observation were similar reaching 49% in both arms surviving at 8 years. Here, we present the long-term oncological and functional outcomes of patients recruited to the study in MSCNCRI along with the quality of life in survivors at >10 years of observation. Methods: Of 180 patients treated in the study in MSCNCRI 88 and 92 pts were randomized to TNT and CRT arms, respectively. The long-term follow-up was performed according to the standard protocol, FACT-C and EORTC QLQ-C30 scales were used to assess the functional outcomes. Results: Median survival in the TNT group and CRT was 115 and 61 months (p=0.191). At the cut-off in March 2023, 53.4% and 61.1% of pts died in the TNT and CRT group (p = 0.375). In the TNT group, 73.9% of deaths were attributed to cancer corresponding to 81.8% in CRT (p = 0.725). Late relapses diagnosed over 5 years from the end of the active treatment were identified in 5 of 94 patients in the follow-up (1 local recurrence in the TNT group, 4 patients with lung metastasis – 3 in TNT with one having also CNS relapse - and 1 in CRT). All late relapses in the TNT group could be salvaged with local therapies. Regarding long-term quality of life, no differences were observed in FACT-C and EORTC QLQ C30 in patients treated with either arm: QLQ C30 – TNT: 50.68 ± 12.74 in the range 34.00- 79.00; CRT: 48.61 ± 11.39 in the range 34.00-70.00 (p = 0.507); FACT-C - TNT: 113.00 in the range 42.00-136.00; CRT: 118.00 in the range 74.00-136.00; p=0.252). No difference in physical, family, and emotional status was observed. At the ultimate observation, stoma was present in 40.5% and 40.6% of TNT and CRT groups, respectively (p>0.999). Conclusions: In this randomized cohort, after more than 10 years of observation TNT led to numerically longer OS than CRT, although this was not statistically significant. The functional outcomes of the long-term survivors are similar in both cohorts. Late relapses are rare but could be salvaged in most cases. This study further supports the use of TNT in patients with locally advanced rectal cancer. Clinical trial information: NCT00833131 .
Survival outcomes for right- versus left-sided colon cancer and rectal cancer in patients receiving regorafenib and/or trifluridine/tipiracil for refractory metastatic colorectal cancer: Findings from the multicenter retrospective ReTrITa study.
67 Background: Several studies show that patients (pts) with colon cancer, particularly pts with right colon cancer (RCC), have lower survival rates than those with rectal cancer. This argues that colorectal cancer should be divided into three clinical entities: RCC, left colon cancer (LCC) and rectal cancer (RC). In refractory metastatic colorectal cancer (mCRC), regorafenib (R) and trifluridine/piracil (T) were found to improve survival. This real-life subgroup survival analysis focused on treatment with R and T, sequential or not, according to the above three primary tumor sites. Methods: Clinical data of pts diagnosed with mCRC and treated with R and/or T between 2012 and 2023 were retrospectively collected at 17 Italian cancer centers. The purpose of this analysis was to compare the overall survival (OS) and progression-free survival (PFS) of pts who received R and/or T as third line and beyond, according to their primary tumor site. Results: The entire ReTrITA study enrolled 1156 patients. 261 (22.5%) of them received the T/R sequence (T/R), 155 (13.4%) the reverse sequence (R/T), 427 (37%) T, and 313 (27.1%) R. For the purpose of this subgroup analysis we identified 381 RCC pts (32.9%), 531 LCC pts (45.9%) and 244 RC pts (21.2%). When comparing the groups treated with the sequential treatment, we observed a statistically significant OS improvement for pts receiving R prior to T: 17,4 vs. 12,2 months (mos) in RCC pts (HR = 0,67; 95% CI = 0,46-0,99; P = 0,0461); 16,1 vs. 15,1 mos in LCC pts (HR = 0,71; 95% CI = 0,51-1,00; P = 0,0559) and 16,6 vs. 11,4 mos in RC pts (HR = 0,57; 95% CI = 0,36-0,89; P = 0,0153). R/T sequence was also found to provide a considerable PFS benefit: 11,8 vs. 7,8 mos in RCC pts (HR = 0,53; 95% CI = 0,37-0,76; P = 0,0006); 11,7 vs. 8,9 mos in LCC pts (HR = 0,64; 95% CI = 0,47-0,88; P = 0,0071) and 10,7 vs. 8,2 mos in RC pts (HR = 0,63; 95% CI = 0,42-0,96; P = 0,0342). The non-sequential administration of R and T had no statistically significant impact on survival outcomes in the three groups. Conclusions: Our real-world subanalysis suggests that the R/T sequence significantly increases survival for pts with primary colon and rectal cancer, even after third-line treatment. Examining the pts groups treated with R and T as monotherapy based on the primary tumour site, however, did not allow us to make any significant conclusions. Treatment decisions should, however, constantly include the patient's characteristics, such as sex, ECOG PS, and the extent of metastatic disease. However, in order to verify our findings, prospective studies are required.
Treatment experiences and decision-making among patients with metastatic colorectal cancer: Results of an online US patient survey.
80 Background: Developing treatment plans for patients (pts) with metastatic colorectal cancer (mCRC) is complex. Using an online survey, we aimed to understand the treatment experience of pts with mCRC, including pt involvement in treatment decision-making. Methods: Adults (≥18 yrs) with mCRC took part in an online survey conducted in the US by The Harris Poll between Jan 17 and Feb 7, 2024. Of 344 respondents, 90 were recruited from patient advocacy groups (PAGs). The 60-question survey explored pts’ experience of mCRC. We report results from questions focused on treatment. Raw data were not weighted and are only representative of the participants. All surveys are subject to sources of error. Results: Of 256/344 pts who received mCRC treatment, chemotherapy and surgery were the most common therapies(Table). Among pts who received therapy, 67% reported their ability to take treatment was impacted by non-medical factors such as finances or mental health. Overall, 58% of pts have had to decide between affording treatment or meeting basic needs, e.g. safe housing, food, transportation, especially Black and Hispanic pts (Table). Of all 344 pts, 87% reported reliance on their healthcare provider (HCP) when making treatment decisions, primarily their oncology surgeon (48%) or oncologist (45%), despite 268 (78%) pts carrying out independent research on new treatments or clinical trials. Although 266 pts (77%) were involved in treatment decision making, 231 pts (67%) wished for more power in the process. Overall, 64 pts (19%) wished for more support from PAGs during treatment, while 59 pts (17%) relied on PAGs to help guide treatment decisions. The most common factors affecting pt treatment decisions related to costs or insurance coverage (52%), impacts on physical health and quality of life (each 39%), fear of being a burden on family (35%), and side effects (32%). Conclusions: Pts with mCRC rely on their HCPs when making treatment decisions and wish for more power in the process. Personal finance and insurance coverage play dominant roles in treatment for mCRC. PAGs are an important resource for treatment information that are underutilized. Treatment experience of pts with mCRC in an online US survey. n (%) All pts N=344 Black pts n=87 c Hispanic pts n=75 c White pts n=158 Received treatment 256 (74) 52 (60) 60 (80) 129 (82) Chemotherapy a 169 (66) 23 (44) 33 (55) 104 (81) Surgery a 147 (57) 23 (44) 32 (53) 86 (67) Radiotherapy a 101 (39) 25 (48) 15 (25) 52 (40) Immunotherapy a 72 (28) 16 (31) 20 (33) 30 (23) Targeted therapy a 61 (24) 12 (23) 14 (23) 30 (23) Other a 13 (5) 0 0 12 (9) Stopped treatment due to overall burden a ,b 92 (36) 28 (54) 33 (55) 27 (21) Had to decide between treatment or basic needs 198 (58) 60 (69) 52 (69) 69 (44) a Among pts who received treatment. b Financial impact, quality of life, etc. c Base size <100 pts; interpret results directionally.
Colorectal cancer metastatic dMMR immunotherapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer 9NRG-GI004/SWOG-S1610).
TPS311 Background: Approximately 45% of dMMR/MSI-H metastatic colorectal cancer (mCRC) in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Within the AtezoTRIBE 8-pt dMMR CRC subgroup treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first progression event at ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up has been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues at U.S. sites. Current accrual (as of 9-20-2024): 100/120. Clinical trial information: NCT02997228 .
Beyond Khorana score 2: Molecular correlates of venous thromboembolism in pancreatic cancer.
751 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with a hypercoagulable state leading to thrombosis. Risk models such as the Khorana score automatically classify PDAC as intermediate-high risk, and recent guidelines recommend consideration of thromboprophylaxis. However, little is known about the molecular correlates of PDAC for venous thromboembolism (VTE). Methods: We examined clinical and genomic data from the prospective multi-institution COMPASS trial (NCT02750657), which enrolled patients with treatment-naïve metastatic PDAC who underwent a fresh tumor biopsy for real-time whole genome and transcriptome sequencing. Laser capture microdissection was performed. Patients underwent restaging scans at 8-week intervals. Detailed chart review was conducted to focus on VTE risk factors, timing of VTE diagnosis, and anticoagulation. We also compared clinical and molecular factors based on timing of VTE diagnosis. Overall survival was defined as time from VTE to death. Results: Of 268 patients enrolled in the COMPASS trial, 166 patients had detailed clinical data available regarding VTE status. 82 patients (49%) developed a VTE, where 16 (20%) had breakthrough clots. Baseline epidemiological variables were similar for those with and without VTE, including no differences between age, sex, BMI, and baseline CA 19-9. No patients were on routine prophylactic anticoagulation. SMAD4 mutations were more frequently seen in the VTE subgroup (57% vs. 40%, p= 0.04), but no differences were seen in other driver genes (KRAS, TP53, CDKN2A), Moffitt subtype, or homologous recombination deficiency status. Patients who developed an early VTE (within 3 months) had a higher baseline CA 19-9 (median 4015 vs. 891, p= 0.02), and none were port-associated. A higher incidence of KRAS wildtype cases (10%) were observed in the early vs. later VTE groups (p= 0.03), but no differences in KRAS allelic status. There were no differences in burden of SNVs, indels, or SVs. Early VTE occurred in 46% of all basal cases, which are typically more aggressive, and only in 37% of classical subtypes. Overall survival was shorter with early VTE (HR 1.74, p= 0.02). Conclusions: A higher incidence of SMAD4 alterations were observed among patients with metastatic PDAC who developed VTE. VTE diagnosed earlier were associated with shorter survival, suggesting that early thromboprophylaxis should be considered at the time of diagnosis. Clinical trial information: NCT02750657 .
GOBLET study: Results of the safety run-in for first-line metastatic pancreatic ductal adenocarcinoma (PDAC) patients treated with pelareorep + modified FOLFIRINOX +/- atezolizumab.
730 Background: Immunotherapies are effective in only the small subset of metastatic PDAC patients with MSI-H or dMMR tumors. Pelareorep (pela) is a non-genetically modified, intravenously administered reovirus that selectively infects cancer cells. It stimulates the expansion of pre-existing tumor-infiltrating lymphocyte (TIL) clones, and it makes tumors visible to the immune system by upregulating interferon-induced gene expression including PD-L1, CXCL9, CXCL10, and CXCL11. PD-L1 upregulation also provides a basis for potential synergy between pela and immune checkpoint inhibitors. Pela combined with gemcitabine/nab-paclitaxel/atezolizumab showed promising tumor responses in mPDAC. Here, we are assessing the safety and preliminary efficacy of pela + mFOLFIRINOX +/- atezolizumab in a new cohort in the ongoing GOBLET study. Methods: GOBLET is a phase 1/2, open-label, Simon two-stage study in patients with advanced or metastatic GI cancers. In this new GOBLET cohort (Cohort 5), patients with newly diagnosed mPDAC are randomized to receive either pela + mFOLFIRINOX or pela + mFOLFIRINOX + atezolizumab. The primary endpoints are safety and objective response rate (ORR). In Stage 1, 15 evaluable patients will be enrolled in each arm. Both arms include a 3-6 patient safety run-in that must be successfully completed prior to opening the study to full enrollment. If pre-specified ORR success criteria are met, one or both arms may be advanced to Stage 2 during which 17 additional evaluable patients/per arm will be enrolled. Results: The 3-patient safety run-in for both arms of Cohorts 5 (6 patients total) have been enrolled, and all patients have completed the required 1-month evaluation period. Cohort 5 safety data have been reviewed by the independent Data Safety Monitoring Board (DSMB). The DSMB identified no safety signals attributable to the combination of pela and mFOLFIRINOX +/- atezolizumab and recommended that enrollment into these arms of Cohort 5 continue without modification. Reported adverse events are consistent with the known toxicities of the components of the treatment regimen. Tumor response results are pending. Conclusions: The results of the GOBLET Cohort 5 safety run-in indicate that pela can be given safely in combination with mFOLFIRINOX +/- atezolizumab to newly diagnosed mPDAC patients. Safety and efficacy of these combination therapies will continue to be monitored (Eudra-CT: 2020-003996-16). Clinical trial information: 2020-003996-16 .
Genetic variants and clinical factors affecting the response to 5-fluorouracil–based treatment in Chilean patients with advanced colorectal cancer.
114 Background: Colorectal cancer (CRC) ranks as the second most common cancer in Chile, affecting both men and women. Late diagnosis results in approximately 25% of patients presenting with metastatic disease, with a five-year survival rate of about 14%. Standard treatment includes tumor resection followed by adjuvant chemotherapy, commonly involving 5-fluorouracil (5-FU) combined with drugs like oxaliplatin or irinotecan. However, patient responses to 5-FU vary greatly due to genetic polymorphisms in enzymes like thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPD), which affect the drug's pharmacokinetics and pharmacodynamics. Polymorphisms in genes related to oxaliplatin elimination and efficacy, such as glutathione-S-transferases (GSTs) and DNA repair enzymes, also play a role. However, the relationship between genetic variants and treatment outcomes remains unclear, often varying by population and cancer stage. Although predictive models for treatment response and risk exist for various diseases, no comprehensive model combining genetic and clinical variables to predict chemotherapy safety in Chilean CRC patients has been developed. Objective: This study aimed to identify relevant genetic variants in the genes TYMS , TYMP , DPYD , GSTP1 , MTHFR , ERCC2 , ABCB1 , ABCC2 , ABCC4 , and ABCG2 , which, along with clinical variables, could help create a predictive model for the safety of 5-FU-based chemotherapy in advanced CRC patients. Methods: A retrospective nested case-control study was conducted on 82 advanced CRC patients. Sixteen genetic variants were analyzed to assess their influence on adverse reactions (ADRs) and their severity, using logistic regression to identify potential associations. Multivariate models were developed to predict chemotherapy safety. Results: Among the 16 variants analyzed in 82 patients, several key findings emerged: The G allele of GSTP1 (rs1695) was found to be protective against neuropathy (OR = 0.147; p = 0.012) but increased the risk of mucositis (OR = 2.27; p = 0.036). The C allele of DPYD (rs1801265) was associated with an elevated risk of neuropathy (OR = 4.50; p = 0.05). The TYMS deletion (rs151264360) provided protection against cutaneous (OR = 0.029; p < 0.0001) and hematological ADRs (OR = 0.098; p = 0.005). Additionally, TYMS deletion was protective against severe toxic ADRs (OR = 0.098; p = 0.005). Two multivariate models were created to predict anemia (p = 0.027) and pain (p = 0.01) development. Conclusions: This study represents an initial step toward developing predictive models for ADRs related to 5-FU, such as neuropathy, mucositis, and hematological and skin toxicities. In the future, these findings may contribute to pharmacogenetic-based dose adjustment models aimed at reducing ADRs in Chilean CRC patients undergoing 5-FU-based treatment.
5-hydroxymethylcytosine as a liquid biopsy biomarker in colorectal cancer.
291 Background: 5-hydroxymethylcytosine (5hmC) is an epigenetic modification which regulates gene expression and is associated with active transcription. The optimization of 5hmC sequencing in cell-free DNA (cfDNA) could therefore enable assessment of gene activity through a liquid biopsy. We aimed to investigate the 5hmC landscape of colorectal cancer (CRC) in plasma-derived cfDNA to evaluate the potential of 5hmC modifications as a liquid biopsy-based biomarker of CRC. Methods: Genome-wide 5hmC modifications were analyzed with a low-input whole-genome 5hmC sequencing method based on selective chemical labeling in cfDNA from 72 CRC patients and 70 healthy samples. Differential 5hmC analysis between CRC and healthy samples was conducted using DESeq2 (padj < 0.05 and log2FC <= -1 and >=1). Low-pass whole genome sequencing (LP-WGS) was performed on all cfDNA samples. Tumor fraction was estimated using ichorCNA to classify samples into high ct-fraction (>=0.1) and low ct-fraction (<0.1) groups. Nucleosome profiling was performed on LP-WGS to reveal chromatin accessibility patterns. Elastic Net Regression (ENR) was applied to identify changes in 5hmC levels for classifying samples as cancerous or healthy. Results: Differential cfDNA 5hmC levels of 139 genes distinguished high ct-fraction CRC (n=16) and healthy samples (n=70). Although the remaining CRC samples (n=56) had similar ct-fractions as the healthy samples, as estimated by ichorCNA, we found a differentially hydroxymethylated gene signature could discriminate between these low ct-fraction CRC and healthy samples. Nucleosome profiling analysis with LP-WGS in cfDNA was used to identify active transcriptional drivers of the genes with increased 5hmC levels. The analysis revealed increased chromatin accessibility near the binding sites for the transcription factor caudal-related homeobox transcription factor 2 ( CDX2 ), a master transcriptional regulator of intestinal cell fate and cancer, in CRC patients relative to healthy samples. Corroborating this, CDX2 and its downstream targets had increased 5hmC levels in cfDNA in CRC relative to healthy samples, consistent with colorectal-derived tumor DNA in CRC plasma samples. Conclusions: Genes with differential 5hmC levels in cfDNA can discriminate CRC and healthy samples. Our 5hmC signature identified CRC samples that did not harbor copy number gains or losses; which is typically used to estimate ct-fraction and routinely included in targeted ctDNA sequencing assays. Integration of 5hmC and LP-WGS can be used to identify gene activation in disease. In the context of CRC, CDX2 displayed increased chromosome accessibility in the promoters of its target genes which in turn displayed increased 5hmC levels. Further studies are aimed at optimizing and validating 5hmC-based biomarkers throughout patient treatment.
A retrospective observational study to evaluate the efficacy of trifluridine/tipiracil ± bevacizumab in metastatic colorectal cancer with MSI-high/deficient MMR.
152 Background: MSI-high (MSI-H)/deficient MMR (dMMR) metastatic colorectal cancer (mCRC) have reported to be resistant to various cytotoxic agents including fluorouracil. On the other hand, preclinical study showed that trifluridine was effective to fluorouracil-refractory dMMR CRC cell lines. Previous studies on trifluridine/tipiracil (FTD/TPI) ± bevacizumab (BEV) for mCRC as later line treatment showed an objective response rate (ORR) of 1.1-5.6% and disease control rate (DCR) of 44-76.6%. However, there are no reports on the efficacy of FTD/TPI± bevacizumab in MSI-H/dMMR mCRC patients. Methods: We retrospectively evaluated the efficacy and safety of FTD/TPI ± BEV as second- or later-line treatment which patients with MSI-H/dMMR mCRC received between June 2012 and January 2023 at the 10 institutions. The primary endpoint was investigator-assessed objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse event rates. We also compared the FTD/TPI + BEV (FTB group) with FTD/TPI (FT group). Results: A total of 18 patients (FTB/FT, 9/9) were included. Patient characteristics were as follows (FTB/FT): median age, 70 (70/70) years; ECOG PS of 0/1, 7 (5/2)/11(4/7); primary tumor location of right side/left side, 12(6/6)/6(3/3); BRAF V600E mutant/wild-type, 6(3/3)/11(6/5); number of previous treatment lines of 1/≥2, 2(1/1)/16(8/8); number of metastatic sites of 1-2/≥3, 8(4/4)/10(5/5); prior use of anti-PD-1 therapy, 10(3/7). Efficacies in the whole population were as follows: ORR, 16.7% (95%CI, 3.6-41.4); DCR, 72.2%; median (m) PFS, 5.5 months; mOS, 11.8 months. Efficacies in each group (FTB vs. FT) were as follows: ORR (22.2% vs. 11.1%) and DCR (88.9% vs. 55.6%) were favored in FTB group than in FT group, while the median PFS were similar between two groups (5.6 months vs. 5.2 months). OS in FTB group was longer than in FT group (median, 18.9 months vs. 7.1 months; hazard ratio, 0.22; p value=0.03). Of 11 (FTB/FT, 7/4) patients who received subsequent treatment, 6 in FTB group and 1 in FT group received anti-PD-1 therapy. The most common grade 3 or more adverse events in each group (FTB vs. FT) were neutropenia (77.8% vs.77.8%), anemia (22.2% vs. 33.3%) and febrile neutropenia (0% vs. 22.2%). Conclusions: FTD/TPI ± BEV showed a promising efficacy and favorable safety. Although this was retrospective study with a small sample size, FTD/TPI ± BEV therapy may have better efficacies for MSI-H/dMMR mCRC than those for MSS/proficient MMR mCRC in previous prospective studies. Next generation sequencing as biomarker analysis using pretreated tissue samples is ongoing.