bluuebunny/crossref_metadata_2025 huggingface dataset:
A retrospective observational study to evaluate the efficacy of trifluridine/tipiracil ± bevacizumab in metastatic colorectal cancer with MSI-high/deficient MMR.
Authors: Inamoto Rin , Hasegawa Hiroko , Sugiyama Keiji , Izawa Naoki , Mitani Seiichiro , Kawakami Takeshi , Yuki Satoshi , Hirano Hidekazu , Mishima Saori , Hamano Tetsutaro , Masuishi Toshiki
Published: January 2025

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.
Optimal duration of neoadjuvant chemotherapy prior to CRS±HIPEC for colorectal cancer: An assessment of survival and postoperative outcomes.
Authors: Bennett Frances Jenkins , Oppat Kailey Morgan , Zaidi Mohammad Yahya , Winer Joshua , Russell Maria C. , Staley Charles A. , Maithel Shishir K. , Concors Seth Jason
Published: January 2025

188

Background:
Cytoreductive surgery (CRS) with or without heated intraperitoneal chemotherapy (HIPEC) represents a viable treatment option for select patients with colorectal cancer peritoneal metastases. Given high recurrence rates after surgery, it is common practice to administer neoadjuvant chemotherapy (NAC). The optimal duration, however, when considering oncologic value and postoperative outcomes, is not known.
Methods:
A single institution database (2009-2024) of colorectal cancer patients that underwent CRS±HIPEC was reviewed. Patients with colorectal cancer undergoing CRS±HIPEC for curative intent (completeness of cytoreduction 0 or 1) with known NAC duration were included. Analysis was stratified by NAC duration of 0-3 months or greater than 3 months. Co-primary outcomes were recurrence free survival (RFS) and overall survival (OS). Secondary outcomes included clinically significant complications, defined as Grade 3 or greater adverse events based on Common Terminology Criteria for Adverse Events Version 5.0.
Results:
From 2009-2024, 108 patients underwent CRS±HIPEC for colorectal cancer. Final analysis included 84 patients that underwent curative intent surgery and had a known duration of NAC ( > 3 months NAC: 55 patients, 0-3 months NAC: 29 patients). Median peritoneal cancer index (PCI) score was similar between the two cohorts ( > 3 months: median PCI 11 versus (vs) 0-3 months: median PCI 12; p = 0.42). Recurrence-free survival was 9 months for the entire cohort and not significantly different based on duration of NAC ( > 3 months: 8 months vs 0-3 months: 15 months, p = 0.14). Overall survival was also similar between both cohorts ( > 3 months: 26 months vs 0-3 months: 37 months; p = 0.11). On univariate analysis, > 3 months of NAC was associated with an increased rate of complications of any severity ( > 3 months: 83.6% vs 0-3 months: 55.2%; p = 0.01), clinically significant complications ( > 3 months: 54.5% vs 0-3 months: 31.0%; p = 0.07), and increased median length of stay ( > 3 months: 10 days vs 0-3 months: 8 days; p = 0.01). When controlling for other perioperative variables on multivariable analysis, > 3 months of NAC trended towards an increased risk of clinically significant complications (HR 1.76, 95% CI 0.59-5.30; p = 0.32).
Conclusions:
Even with a similar disease burden, as measured by PCI, an extended duration of neoadjuvant chemotherapy prior to CRS±HIPEC does not appear to be associated with any improved recurrence-free or overall survival. Conversely, postoperative outcomes are worse with higher complication rates and increased length of stay. Thus, despite high recurrence rates after CRS±HIPEC for this disease, it still appears that in well selected patients, an extended duration of neoadjuvant chemotherapy may not be the best treatment strategy.
Tumour-free ctDNA detection as a decision tool to support organ preservation in node-negative rectal cancer undergoing neoadjuvant chemotherapy, excision, and observation in the phase II NEO trial (CCTG CO.28).
Authors: Loree Jonathan M. , Titmuss Emma , Brown Carl J. , Rich Thereasa A. , Tu Dongsheng , Jonker Derek J. , O'Callaghan Christopher J. , Kennecke Hagen Fritz
Published: January 2025

20

Background:
In the NEO trial (CCTG CO.28, NCT03259035) patients with node negative (N0) T1-T3 rectal cancer were treated with neoadjuvant CAPOX/FOLFOX and transanal excision surgery (TES) with the goal of organ preservation. Patients without documented response following neoadjuvant chemotherapy were recommended total mesorectal excision (TME). We present a post-hoc assessment of ctDNA detection in this early-stage population and correlate kinetics with response and outcomes.
Methods:
Fifty-eight patients enrolled in CO.28. Whole blood was collected in EDTA tubes and processed for future ctDNA analysis at up to six timepoints: pre-chemotherapy, after neoadjuvant chemotherapy (and pre-TES), yearly during surveillance for 3 years and upon progression. A total of 195 samples were analyzed with the Guardant Reveal™ assay: a tissue-free epigenomic assay leveraging >20,000 epigenomic regions for ctDNA detection.
Results:
Of 48 available pre-treatment samples, ctDNA was detected in 22 (46%). Sensitivity by T-stage was 14% (1/7) for T1, 53% (17/32) for T2, 44% (4/9) for T3 cancers. ctDNA detection was lower following neoadjuvant chemotherapy (4/46, 9%, p<0.001 vs pre-chemotherapy). Of 41 patients with paired pre- and post-chemo samples, 49% (20/41) had undetectable ctDNA at both timepoints, 44% (18/41) had reduced tumour fraction following chemotherapy, the majority of which completely cleared ctDNA (94%; 17/18) and 7% (3/41) had an increased tumour fraction following chemotherapy (67%, 2/3 changing from negative to positive), all three of whom failed to respond to neoadjuvant chemotherapy and had TME recommended (100%). In contrast, of those that cleared ctDNA following chemotherapy, 35% had TME recommended (6/17, p=0.074). Of five recurrences (3 distant, 2 local), all had negative or reduced ctDNA tumour fraction during neoadjuvant therapy before surgical intervention. Among patients with local relapse who were managed with TES, 1/2 (50%) had detectable ctDNA at the time of local progression. No samples were available for those with distant recurrences (3/5) at time of relapse.
Conclusions:
The Guardant Reveal tissue-free assay was able to detect ctDNA even in this extremely early-stage cohort and identified cancers with inadequate response to therapy and in whom TME was recommended. A tissue-free approach may support timeliness of ctDNA results that would support ctDNA as an additional decision tool with endoscopic and MRI assessments to increase physician and patient comfort with organ preservation. Clinical trial information: 03259035.
Oncomine panel testing in the clinical management of colorectal cancer: An Irish experience.
Authors: O Reilly Mary , Moran Bruce , Sheahan Kieran , Winter Des C , Kolch Walter , Keane Fergus , McDermott Raymond S. , Krstic Aleksandar
Published: January 2025

212

Background:
Early onset colorectal cancer (EOCRC) is defined as colorectal cancer (CRC) in those under the age of 50. It has been hypothesized that the molecular signatures of EOCRC could differ from those of late onset CRC (LOCRC). Next Generation Sequencing (NGS) using the Oncomine Precision Assay is a useful tool to guide treatment decisions based on the presence or absence of oncogene drivers. While not all of these mutations currently influence the clinical management of CRC patients, ongoing research on the function of these genes and the development of new drugs could offer insights into patient prognosis, treatment choices and prediction of therapy resistance.
Methods:
Of >1500 CRC identified between 2010 and 2024, we investigated the clinical and genetic characteristics of 38 EOCRC and 41 LOCRC cases. All cases were microsatellite stable and staged I-III. NGS was performed with the Ion Torrent Genexus integrated platform using the Oncomine 45-gene Precision Assay panel. DNA hotspot mutations and copy number variations (CNVs) were assessed, followed by the classification of clinically relevant mutations using the genetic variant OncoKB database.
Results:
There were 38 EOCRC and 41 LOCRC cases. The age range was 27 to 49 and 50 to 91, with median ages of 44 and 72, in the EOCRC and LOCRC groups, respectively. Based on the stratification of NGS mutation levels as per the OncoKB classification, all patients in both groups (100%) had level 1 actionable mutations. NRAS wild type (WT) status was present in 100% of patients in both groups. However, differences were observed in KRAS status: 84% (32/38) of EOCRC were KRAS WT, while only 65% (27/41) of LOCRC were KRAS WT. While 3 % (n=1) of the EOCRC cohort had an ERBB2 amplification, none were detected in the LOCRC group. BRAF V600E mutations were present in 11% (4/38) of EOCRC and 12% (5/41) of LOCRC. Level 4 mutations were detected in 18% (n=7) of EOCRC, all of which were PIK3CA mutations, while these were seen in 24% (n=10) of the LOCRC group, including 9 PIK3CA mutations and 1 FGFR1 mutation. Regarding concurrent mutations, 2 patients in the EOCRC group had two mutations each: one with concurrent KRAS and PIK3CA mutations, and another with concurrent JAK2 and KRAS mutations. The LOCRC group had a higher incidence of concurrent mutations, with 8 patients affected: 6 had concurrent KRAS and PIK3CA mutations, and 2 had concurrent BRAF and PIK3CA mutations.
Conclusions:
Our study demonstrates that EOCRC have higher KRAS WT status and fewer concurrent mutations compared to LOCRC, who exhibit more frequent KRAS non-G12C oncogenic mutations. It also underscores the importance of routine NGS mutation panel analysis in CRC management. Additionally, identifying specific mutations in patients that relapse can guide targeted therapies, potentially improving outcomes and offering personalized treatment options.
Can overall survival (OS) benefit be predicted from improvements in progression-free survival (PFS) for previously untreated metastatic colorectal cancer (mCRC)?
Authors: Roodhart Jeanine , Dave Kiran , Dixon Matthew , Kurt Murat , Pushkarna Divya , Pourrahmat Mir-Masoud , Fazeli Mir Sohail
Published: January 2025

222

Background:
With improvements in treatment of mCRC, OS maintains its gold standard efficacy measure but takes longer to mature than intermediate endpoints. This study analyzed the association between treatment effects on PFS and OS using aggregate-level data from RCTs in previously untreated mCRC patients.
Methods:
A systematic literature review identified RCTs in previously untreated mCRC patients published from 2010–2021 reporting hazard ratios on PFS (HR
PFS
) and OS (HR
OS
). All treatments in comparison to chemotherapy alone or chemotherapy with anti-VEGF (bevacizumab) or anti-EGFR (cetuximab) targeted therapy were considered. Correlation between HR
PFS
and HR
OS
was evaluated using bivariate random-effects meta-analysis (BRMA) and weighted linear regression (WLR). Predictive performance of the surrogacy equations from WLR was assessed using leave-one-out cross-validation (LOOCV). Surrogate threshold effects (STE), defined as the minimum PFS benefit that would translate into a statistically significant OS benefit with 95% probability, were also derived to gauge the practical utility of the models. Primary analysis consisted of all included trials. Sensitivity analyses omitted trials that (I) had anti-EGFR medications, (II) had anti-VEGF medications, (III) violated proportional hazards assumptions, and (IV) permitted treatment crossover.
Results:
In the primary analysis 47 trials were included. The estimated correlation between PFS and OS was 0.67 (95% CI: 0.48–0.80) using BRMA and 0.70 (95% CI: 0.48–0.84) using WLR. The surrogacy equation derived from WLR was log(HR
OS
) = −0.03 + 0.56 log(HR
PFS
) with a statistically insignificant intercept and significant slope. Estimated STEs corresponding to sample sizes of 200 and 300 patients were 0.55 and 0.62, respectively. Observed HR
OS
’s were within their 95% prediction intervals predicted from HR
PFS
for 93.6% of studies in LOOCV. Sensitivity analyses produced moderate correlations with >90% coverage in LOOCV (Table).
Conclusions:
Moderate correlations were found between HR
PFS
and HR
OS
using both modeling approaches, highlighting the stability of the findings. Cross-validations of surrogacy equations indicated promising predictive value of PFS benefit for OS benefit in previously untreated mCRC.

Analysis Set​
# of Studies​
Correlation (95% CI)
STE
LOOCV​Coverage Rate​

BRMA

WLR

N = 200

N = 300

Sensitivity Analysis I​
34​
0.75 ​(0.57, 0.86)​
0.78 ​(0.55, 0.90)​
0.55​
0.61​
94.1​%

Sensitivity Analysis II​
14​
0.44 ​(-0.08, 0.77)​
0.62 ​(-0.05, 0.90)​
0.44​
0.52​
92.9​%

Sensitivity Analysis III​
36​
0.61 ​(0.36, 0.77)​
0.59 ​(0.26, 0.80)​
0.46​
0.55​
94.4​%

Sensitivity Analysis IV
43​
0.68 ​(0.48, 0.81)​
0.67​(0.41, 0.83)​
0.52​
0.60​
93.0​%
Phase II study of cabozantinib and nivolumab in refractory metastatic microsatellite stable (MSS) colorectal cancer (CRC).
Authors: Leal Alexis Diane , Blatchford Patrick Jud , Kim Sunnie S. , Lentz Robert William , Kemme Douglas Jerome , Russen McKenna , Friedrich Tyler , Mathew Lynn , Hoyer Robert John , Kono Scott Arthur , Baiyee Toegel Emily , Bagby Stacey M , Dominguez Adrian , Davis S. Lindsey , Pitts Todd , Lieu Christopher Hanyoung , Messersmith Wells A.
Published: January 2025

229

Background:
Current data suggest that combining tyrosine kinase inhibitors with immune checkpoint inhibitors may be a promising treatment strategy in patients with metastatic MSS CRC. This prospective, open-label, single-arm, phase II study (NCT04963283) evaluated the efficacy of cabozantinib in combination with nivolumab in patients with metastatic refractory MSS CRC.
Methods:
Patients with metastatic/unresectable MSS CRC who were refractory to chemotherapy in the 3
rd
line setting and beyond were eligible. Patients were treated with cabozantinib 40 mg orally daily and nivolumab 480 mg IV every 28 days. Tumor assessments were obtained every 8 weeks for the first 16 weeks, and then every 12 weeks thereafter. Response was assessed via RECIST v1.1. The primary endpoint was 16-week disease control rate (16-wk DCR); secondary endpoints were objective response rate (ORR), progression free survival (PFS), overall survival (OS), safety and tolerability, and correlative studies (to be presented at a future date).
Results:
Between June 2021 and January 2024, 49 pts were enrolled; 63% were male; median age 55 [50-64]. Median prior treatment regimens were 4 [2-14]. Most patients (84%) had not received prior trifluridine/tipiracil; only 1 patient had received prior regorafenib. The 16-wk DCR was 40% (19/47) (95% CI 0.264 – 0.557). The 16-wk ORR was 8.5% (4/47) (95% CI 0.024 – 0.204). mPFS was 3.4 months (95% CI 1.8-5.0) and mOS was 10.9 months (95% CI 4.7-13.8). Thirty nine percent of patients experienced a serious adverse event (SAE), with 4% Gr 1, 37% Gr 2, 35% Gr 3 and 4% Gr 4; there were no Gr 5 treatment related adverse events. The most common AEs were diarrhea (53%), fatigue (43%), hypothyroidism (31%), weight loss (29%), nausea (29%), and hypertension (27%). Two patients remain on study at time of abstract submission.
Conclusions:
The combination of cabozantinib and nivolumabwas well tolerated and provided modest benefit in a population of patients with metastatic, chemotherapy refractory, MSS CRC.
Clinical trial information: NCT04963283
.
Preclinical analysis and clinical validation to identify biomarkers for trifluridine/tipiracil (FTD/TPI) efficacy with or without bevacizumab in patients with metastatic colorectal cancer.
Authors: Suenaga Mitsukuni , Mashima Tetsuo , Kawata Naomi , Dan Shingo , Seimiya Hiroyuki , Yamaguchi Kensei
Published: January 2025

230

Background:
We previously identified candidate biomarkers for FTD/TPI efficacy through preclinical and translational studies in patients with metastatic colorectal cancer (mCRC). Recent studies reported that FTD/TPI plus bevacizumab (BEV) improved survival compared to FTD/TPI alone. This study evaluated the clinical significance of these biomarkers in patients with refractory mCRC receiving either FTD/TPI plus BEV or FTD/TPI alone.
Methods:
Candidate biomarkers were selected based on our transcriptomic and cell biological analyses. We validated these biomarkers in mCRC patients treated with FTD/TPI plus BEV (cohort A) or FTD/TPI alone (cohort B). Blood samples were collected at baseline (BL), before the second cycle (2nd), and progressive disease (PD), with serum biomarker levels measured using ELISA. Change patterns were classified as ‘increased’ or ‘decreased’ from BL. To address the unbalanced distribution of baseline characteristics between cohorts, propensity score matching (PSM) was performed.
Results:
A total of 112 patients were included, with 34 in each cohort after PSM. Cohort A showed significantly longer overall survival (OS) (14.4 vs 6.2 months, HR 0.53, 95%CI: 0.30-0.93) and higher disease control (DC) (58.8 vs 34.4%, P=0.047) compared to cohort B. In univariate analysis, increased IL-8 or AREG at 2nd and increased IFI16 at PD were associated with poorer clinical outcomes. Grade ≥3 neutropenia (NEU) was linked to better survival in both cohorts. Multivariable analysis identified decreased AREG and Grade ≥3 NEU as better markers for progression-free survival and OS. OS was significantly longer in cohort A compared to B (12.8 vs 5.8 months, HR 0.43, 95%CI: 0.21-0.89) when IL-8 increased at 2nd. Cohort A also had longer OS compared to cohort B when EREG (12.8 vs 6.2 months, HR0.27, 95%CI: 0.11-0,65) or AREG (14.2 vs 9.7 months, HR 0.40, 95%CI: 0.17-0.95) decreased at 2nd. There was no significant interaction between the regimen and biomarkers (IL-8, EREG, and AREG) for OS.
Conclusions:
Our data suggest that AREG may serve as a prognostic marker for FTD/TPI efficacy. Changes in IL-8, EREG and AREG potentially contribute to the extended survival benefit of combining BEV with FTD/TPI.
Proto-oncogene HRAS transcript level and overall survival in stage II and III colorectal cancer.
Authors: Kim Donghyun , Sharif Saima , Raygoza Garay Juan Antonio , Churchman Michelle L. , Rounbehler Robert J. , Bhakta Avinash S. , Boland Patrick M , Cavnar Michael J. , Hatoum Hassan , Huang Lyen C. , Kim Joseph , Kim Richard D. , Lentz Robert William , Mukherjee Sarbajit , O'Donnell Mary , Quartey Benjamin , Reilley Matthew , Salhia Bodour , Schneider Bryan P. , Chan Carlos H.F.
Published: January 2025

231

Background:
Mutational landscape is prognostic in colorectal cancer (CRC). Driver mutations in the RAS proto-oncogenes such as KRAS and NRAS portend poor survival outcomes, whereas HRAS mutations are extremely rare and their prognostic value remains uncertain. The prognostic implication of RAS gene activity at the transcript level is also obscure. Here, we retrospectively review stage II and III CRC tumor RNA-Seq data and demonstrate that high transcript levels of HRAS are associated with superior overall survival (OS).
Methods:
Tumor RNA-Seq of 734 stage II and III CRC cases and their associated clinical data were retrieved from the ORIEN AVATAR database (Aster Insights). Transcript level was determined by batch-corrected TPM (transcripts per million) of each gene, and cohort median was used as a reference to determine “high” versus “low” in subgroup analyses. The p-value and hazard ratio (HR) derived from Kaplan-Meier survival analysis are log-rank.
Results:
The 4-year HR for death in patients with “very high” HRAS transcript level (top 5%) was 0.15 (95% CI 0.07-0.34, p=0.03) compared to the rest, and this superior OS was independent from TNM stage or peri-operative 5-FU treatment history. In subgroup analyses, “high” HRAS expression was associated with superior OS only in patients with concomitant “low” KRAS expression in the absence of pathologic KRAS mutations in codons 12, 13 and 61 – the 5-year HR in “low” KRAS group was 0.42 (95% CI 0.18-0.96, p=0.03) compared to “high” KRAS group. NRAS transcript level did not influence OS. When further sub-grouped based on primary disease location, this superior OS was present only in the right-sided primary disease group with 5-year HR of “low” KRAS group at 0.17 (95% CI 0.03-0.99, p=0.06) compared “high” KRAS group.
Conclusions:
Contrary to the notion that RAS family genes are proto-oncogenic, we demonstrate that high HRAS transcript levels are associated with superior OS in stage II and III CRC. The high HRAS-associated OS benefit was most pronounced in patients with right-sided primary expressing low KRAS transcript levels in the absence of pathologic KRAS mutations. We speculate that when expressed at high levels, HRAS may counteract proto-oncogene KRAS but not oncogene KRAS at the transcript level. The potential of HRAS as a prognostic biomarker should be explored further.
PK/PD analyses of circulating tumor DNA (ctDNA) in patients with metastatic colorectal cancer (mCRC) treated with telisotuzumab adizutecan (ABBV-400).
Authors: Abdelgawad Ibrahim , Vasilopoulos Athanasios , Neagu Aristide Martha Raluca , Freise Kevin Jay , Parikh Apurvasena , Biesdorf de Almeida Carla
Published: January 2025

233

Background:
Telisotuzumab adizutecan (ABBV-400) is an antibody drug conjugate (ADC) consisting of a c-Met targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor payload adizutecan. The ongoing first in human phase 1 trial (Study M21-404; NCT05029882) shows that ABBV-400 has encouraging radiographic response and ctDNA molecular response (MR) as monotherapy in patients with advanced solid tumors, including mCRC. Herein, correlation between ABBV-400 exposures and % change in ctDNA from baseline and PK/PD analyses using MR are presented for mCRC patients. Impact of c-MET expression and
MET
amplification (
MET
-amp) status on exposures was also evaluated.
Methods:
Analyses utilized preliminary data in mCRC patients (N=122) from study M21-404 where subjects were treated with ABBV-400 (1.6 – 6.0 mg/kg Q3W). Serial PK samples were collected in cycles 1 (C1) and 3 (C3) and sparse samples across other cycles. C1 exposure metrics (C
max
, C
avg
, and C
trough
) for both ABBV-400 conjugate and unconjugated payload were obtained by non-compartmental PK analysis. Baseline and C3 day 1 plasma samples were collected and analyzed using the Guardant INFINITY assay for biomarker analysis. ctDNA (circulating tumor fraction [cTF]) was estimated based on 1) variant allele frequency of somatic mutations in a 74 gene panel and 2) methylation signals across targeted regions of the Guardant INFINITY methylation panel. MR was defined as a 50% decrease in cTF from baseline. PK/PD correlations with % change in cTF at C3 and MR at C3 were evaluated. c-Met protein expression was assessed by IHC (VENTANA MET SP44 RxDx Assay) and
MET
-amp status was based on available local testing results and retrospective ctDNA testing.
Results:
Higher exposures of ABBV-400 conjugate and payload (primarily C
avg
for both analytes and C
max
for conjugate) correlated with greater decrease in % change in cTF at C3 from baseline, as assessed by the 74 gene panel (N =66) or methylation panel (N=74). PK/PD analysis showed that higher exposure was strongly correlated with higher probability of MR (n=66-74, nominal p < 0.05). ABBV-400 conjugate and payload exposures were comparable across c-Met expression H-score (range 9 – 295), cut-offs (≥90% with 1+ intensity, ≥50% with 2+, ≥10% with 3+, ≥25% with 3+, and ≥50% with 3+), and
MET
-amp status.
Conclusions:
Exposure-response analyses have previously shown correlation between ABBV-400 conjugate exposures and probability of efficacy (objective response rate) as well as safety in mCRC subjects. The current PK/PD analyses demonstrate that higher ABBV-400 conjugate and payload exposures are also correlated with liquid biopsy data, i.e., ctDNA and MR based on ctDNA. c-MET expression and MET-amp did not have impact on ABBV-400 exposures.
Clinical trial information: NCT05029882
.
Clinical relevance of tumor fraction assessment from circulating tumor DNA in metastatic colorectal cancer.
Authors: Morris Van K. , Quintanilha Julia , Elvin Julia A , Graf Ryon P , Kopetz Scott
Published: January 2025

237

Background:
Both tissue (TBx) and liquid (LBx) biopsies are indicated for detecting actionable alterations in metastatic colorectal cancer (mCRC). LBx is easier to obtain and often has faster turnaround time, but its informative results depend on the ctDNA tumor fraction (TF) content. We aimed to (1) evaluate the concordance between LBx and TBx in CRC; and (2) determine baseline lab and clinical factors associated with TF.
Methods:
CRC patients (pts) with both tissue and liquid Foundation Medicine comprehensive genomic profiling within an interval of up to 90 days between samples collection were analyzed. Positive percent agreement (PPA) and negative predictive value (NPV) for RAS (KRAS/NRAS) and BRAFV600E detection were calculated with tissue as reference. Clinical data was obtained by the US-wide de-identified Flatiron Health-Foundation Medicine real-world clinicogenomic CRC database, from ~280 cancer clinics (~800 sites of care) between 1/2011-12/2023. mCRC pts with LBx collected up to 60 days prior to therapy (Tx) start were analyzed for association between TF and baseline factors using logistic regression with TF≥1% as the binary outcome. Baseline factors include age, ECOG, race/ethnicity, line of therapy, practice type, metachronous vs. synchronous disease, tumor side, albumin, alkaline phosphatase (AP), serum creatinine, hemoglobin, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio, opioid and steroid pre-Tx. Foundation Medicine’s ctDNA TF is a composite algorithm prioritizing aneuploidy at higher levels to avoid germline signal and prioritizing variant allele frequency of canonical alterations at lower levels to maximize dynamic range.
Results:
A total of 402 pts had TBx and LBx (268 [67%] TF≥1% and 134 [33%] TF<1%). Without accounting for TF, the overall PPA for RAS and BRAFV600E was 77% and 83%, and the NPV was 65% and 99%. In LBx with TF≥1%, the PPA for RAS and BRAFV600E was 99% and 100%, and NPV was 98% and 100%. In contrast, for TF<1% samples, the PPA for RAS and BRAFV600E was 37% and 50%, and NPV was 57% and 97%. Of the 633 pts with LBx collected prior to Tx, 474 (75%) had TF≥1%. TF≥1% was independently associated with ECOG 1+ (odds ratio [OR]: 1.58, p=0.038), community oncology care site (OR: 2.58, p=0.002), elevated levels of AP (OR: 3.00, p<0.001) and LDH (OR: 3.97,p=0.002). TF≥1% was less likely to occur in right-side tumors (OR: 0.53, p=0.012) and metachronous disease (OR: 0.48, p<0.001).
Conclusions:
Approximately 70% of LBx samples from CRC pts have TF≥1%, with near-perfect concordance for RAS/BRAFV600E. For LBx with TF<1%, interpretation of negative results can be challenging due to low tumor shedding, especially for RAS mutations, where 43% may be false negatives and a subsequent TBx will provide more confidence in the negative results. Clinical factors such as right-sided tumors and metachronous disease may help anticipate low TF and guide decisions to pursue TBx.
Disparities in stage of diagnosis of colon cancer: Differences by Hispanic background, race, and ethnicity.
Authors: Varvoglis Dimitrios N. , Agala Chris B , Perreira Krista M. , Guillem Jose G.
Published: January 2025

24

Background:
Given noted heterogeneity in Hispanic adults, cancer outcomes reported in aggregate may not detect disparities within specific Hispanic subgroups. The objective was to assess whether any potential differences in colon cancer (CC) stage at diagnosis among patients with Hispanic background (HBackground) could be explained by differences in socio-economic determinants of health (SDOH) including income, education and insurance status.
Methods:
The National Cancer Database was queried for patients diagnosed with CC from 2004 to 2021. Two logistic regression models generated adjusted odds ratios of late-stage (III-IV) vs early-stage (I-II) CC at diagnosis, disaggregated either by HBackground or R&E, compared to non-Hispanic White (NHW) patients. Model 1 controlled for patient/facility characteristics; Model 2 controlled for additional SDOH.
Results:
Of the 442,742 CC patients identified, 6% were Hispanics. Compared to NH adults, Hispanic patients were more likely (6% higher odds, p<0.0001) to present with late-stage CC. When Hispanic patients were disaggregated by HBackground, some were more likely (Mexicans 16%; Cubans 20% and South/Central Americans 12%) than NHW adults to present with late-stage CC while others (Puerto Ricans and Dominicans) were not. Disaggregation by R&E indicated that only Hispanic-White patients were more likely (12%) to present with late-stage disease than NHW patients. Controlling for SDOH, R&E differences in stage at diagnosis persisted but HBackground differences became insignificant (Table).
Conclusions:
Disaggregation of Hispanic adults by HBackground identifies specific subgroups at increased risk for late-stage CC at diagnosis. Understanding modifiable SDOH may identify opportunities for improving early detection of CC and outcomes in specific Hispanic subgroups.

Odds of presenting with late-stage colon cancer of “Hispanic” patients disaggregated by race and ethnicity or Hispanic background compared to non-Hispanic Whites.

Disaggregation based on:
Model 1: Adjusted for age, facility type, year of diagnosis, and Charlson-Deyo comorbidity

Model 2: Adjusted for age, facility type, year of diagnosis, Charlson-Deyo comorbidity, neighborhood income, neighborhood education, and insurance status

aOR (95% CI)
p-value
aOR (95% CI)
p-value

Non-Hispanic White (n=418,046)
(ref)

(ref)

Hispanic White (n=24,058)
1.12 (1.09, 1.15)
<.0001
1.04 (1.01, 1.07)
0.01

Hispanic Background

Mexican (n=3,612)
1.16 (1.08, 1.24)
<.0001
1.05 (0.97, 1.13)
0.25

South/Central American (n= 1,734)
1.12 (1.02, 1.24)
0.02
1.01 (0.91, 1.12)
0.83

Cuban (n=937)
1.20 (1.05, 1.36)
0.001
1.11 (0.97, 1.27)
0.13

Puerto Rican (n=1,280)
1.07 (0.95, 1.19)
0.28
1.01 (0.90, 1.14)
0.88

Dominican (n=465)
1.14 (0.94, 1.39)
0.18
1.02 (0.83, 1.25)
0.85

aOR, Adjusted odds ratio; CI, confidence Interval.
Impact of
RAS
and
BRAF
heterogeneity on the efficacy of EGFR blockade in patients with metastatic colorectal cancer.
Authors: Matsuhashi Nobuhisa , Yamada Takeshi , Nagasaka Takeshi , Kataoka Kozo , Sakamoto Kazuhiro , Koda Keiji , Hiramatsu Kazuhiro , Matsuoka Hiroshi , Kuramochi Hidekazu , Ishida Hideyuki , Yokomizo Hajime , Kagawa Yoshinori , Suenaga Mitsukuni , Matsuda Akihisa , Nagata Jun , Ishimaru Kei , Kosugi Chihiro , Takahashi Takao , Yoshida Hiroshi , Hirata Keiji
Published: January 2025

255

Background:
Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in metastatic colorectal cancer (CRC) patients without
RAS
nor
BRAF
mutations. However, some patients without RAS or BRAF mutations in their primary tumors may develop these mutations in metastatic tumors (heterogeneity). Circulating tumor DNA (ctDNA) can reflect this heterogeneity in metastatic tumors. Here, we evaluated the efficacy of EGFR blockade in patients who had no
RAS
or
BRAF
mutations in their primary tumors but did have them in ctDNA.
Methods:
We prospectively enrolled 100 patients with confirmed metastatic CRC without
RAS
or
BRAF
mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy including EGFR blockade. We obtained ctDNA from each patient before they started chemotherapy.
RAS, BRAF (V600E),
and
PIK3CA
mutations were detected using digital PCR.
Results:
One of the 100 cases were excluded due to protocol violation. In the ctDNA obtained before starting chemotherapy,
RAS,
BRAF,
and
PIK3CA
mutations were detected in 12, 4, and 6 patients, respectively. No patients had both
RAS
and
BRAF
mutations in their ctDNA; however, one patient had both
BRAF
and
PIK3CA
mutations and one had both
RAS
and
PIK3CA
mutations. Eighty-nine patients had measurable tumor lesions. Among these, 3 experienced a complete response (CR), 71 had a partial response (PR), 13 had stable disease (SD), and 2 had progressive disease (PD). The response rates for patients with
RAS
or
BRAF
mutations and for patients with neither mutation were 81% and 83%, respectively (P=0.73). Median progression-free survival (PFS) for patients with
RAS
or
BRAF
mutations and those without mutations were 251 days and 216.5 days, respectively (P=0.82). The presence or absence of PIK3CA mutations did not affect the response rate or PFS.
Conclusions:
Previously, we reported that the incidence of
RAS
and
BRAF
heterogeneity were 10% (1) and 4% (2). In the present study,
RAS
and
BRAF
heterogeneity were 12% and 4%, respectively. The heterogeneity of
RAS
and
BRAF
mutations had no effect on the response rate and PFS of EGFR blockade as first line chemotherapy. The effect of heterogeneity on the overall survival is of great interest; however, about half of the patients are still alive. 1. Yamada T, et al. Cancer Science 2016. 2. Ueda K, et al. Eur J Surg Oncol 2022.
Clinical trial information: UMIN000031177
.
Bragg peak proton irradiation and ATM inhibition for rectal cancer.
Authors: Callaghan Cameron Matthew , Dragojevic Sonja
Published: January 2025

259

Background:
Rectal cancer patients with a complete response (CR) after chemotherapy and radiotherapy may opt for non-operative management. Currently only 20-40% of patients reach a CR. Escalating the dose of radiation may increase the risk of toxicity. ATM inhibitors (ATMi) are potent radiosensitizers in colorectal cancer (CRC). Proton irradiation exhibits an entrance portion of the beam (ENT) where dose is deposited sparsely and a Bragg Peak (BP) with virtually no ‘exit dose’ thereafter. ATMi renders cells uniquely hypersensitive to proton BP, and BP+ATMi may increase the response of Mismatch Repair proficient (pMMR) rectal cancer to immunotherapy.
Methods:
Tumor efficacy and immunogenicity was assessed using clonogenic survival, γH2AX foci, micronuclei, and cytoplasmic cGas assays after indicated IR modalities +/-ATMi. Normal tissue toxicity was assessed via murine models of non-tumor bearing BALB/c after whole-abdominal irradiation (WAI) after indicated IR modalities +/- ATMi via acute weight loss, FITC/Dextran assay, and Radiation Injury Score (RIS, Scale 0-18) in jejunal and rectal samples at 4 days post-IR.
Results:
ATMi decreased clonogenic survival across all types of radiation, but the effect was most pronounced with BP protons. BP+ATMi also significantly increased unresolved γH2AX foci, micronuclei, and cytoplasmic cGas compared to ENT+ATMi. Normal tissue toxicity studies demonstrated that BP+ATMi did not significantly increase acute weight loss, RIS in jejunal or rectal tissue; but did increase FITC/Dextran intestinal permeability.
Conclusions:
Inhibition of ATM preferentially radiosensitized BP protons compared to x-rays or ENT protons in CRC but not in normal tissue based on weight loss and histopathological evaluation.

Differential tumor efficacy and normal tissue toxicity after x-ray, entrance and Bragg Peak Protons +/- ATM inhibitor.

A
B
C
D
E
F
G
H
I
J

DMSO
1
1
1
2.9
1.5
8764
96.4
10
0.3
0.2

ATMi
0.873
0.842
0.723
8.2
3.0
16300
98.5
5.8
0.7
0.8

x-ray
0.615
0.751
0.109

82.4
6.2
4.8
1.0

x-ray+ATMi
0.123
0.344
0.011

80.0
14.4
5.2
1.5

ENT protons
0.293
0.515
0.080
10.2
5.8
10429
78.5
6
2.9
1.5

ENT+ATMi
0.091
0.066
0.013
15.1
7.2
12274
73.0
23.8
5.2
3.8

BP protons
0.213
0.340
0.032
12.0
12.6
7192
75.6
24.6
4.1
3.7

BP+ATMi
0.074
0.038
0.004
22.7
16.2
43677
73.6
310.4
5.3
4.3

Clonogenic survival of pMMR colorectal cancer cell lines after IR (4 Gy) +/- 10nM AZD1390 (ATM inhibitor) ofA) HT29, B) CT26, and C) SW480 cell lines. D) γH2AX foci at 24 hours post-IR in HT29. E) Micronuclei, and F) cytoplasmic cGas integrated density per cell via immunofluorescence in SW480 72 hours post-IR. WAI (10Gy/1 fraction) was delivered to non-tumor bearing BALB/c mice which were followed for G) acute weight loss (% from baseline), and H) FITC/Dextran permeability assay. Tissue samples were graded for Radiation Injury Score in I) jejunal, and J) rectal samples at 4 days post-IR (n=5 per cohort, 3 samples per mouse). Figures are means of triplicate data.
A comparison of real-world outcomes by mismatch repair status in patients with stage II/III rectal cancer in the Netherlands.
Authors: Lunenberg Renee A , Franken Ingrid , van der Baan Frederieke H , Sijtsma Femke P C , Vink Geraldine R , Koopman Miriam , Intven Martijn P.W. , Braat Manon , Moons Leon , Lacle Miangela M , Elferink Marloes , Boklage Susan , Garside Jamie , van Wuijtswinkel Rob , Roodhart Jeanine
Published: January 2025

260

Background:
A subset of rectal tumours (~3–5%) have mismatch repair deficiency (dMMR); the remaining are classified as MMR proficient (pMMR). A recent trial for stage II/III dMMR rectal cancer (RC) showed that 6 months of neoadjuvant treatment with dostarlimab, a programmed cell death protein 1 inhibitor, induced a 100% clinical complete response rate and allowed for organ preservation. Using real-world data from the Netherlands, a dMMR patient cohort was compared to a matched pMMR cohort to assess if clinical outcomes differed, even after matching for baseline characteristics.
Methods:
Utilizing data from the Netherlands Cancer Registry, this retrospective analysis assessed patients with stage II/III RC treated from 2015–2022 with known MMR status. The dMMR cohort was matched 1:2 to a cohort of pMMR patients on age, year of diagnosis, tumour clinical (cT) stage, and node clinical (cN) stage. Event-free survival (EFS; defined as first occurrence of locoregional failure, distant metastasis, a new primary colorectal tumour, or death from any cause) and overall survival (OS) were compared using Kaplan-Meier methodology and a univariable Cox model.
Results:
Among the 7939 patients included, 184 (2.3%) had dMMR tumours. After matching and a loss of 8 dMMR patients due to ineligibility, 176 dMMR patients were compared to 363 pMMR patients. Matching successfully removed differences in age, cT, and cN stage; however, dMMR patients continued to have more BRAF mutants (p=0.014), more poorly differentiated tumours (p<0.001) and more variation in histology (p=0.01). dMMR patients had a statistically significant lower risk of experiencing an event (hazard ratio [HR] 0.54 [95% confidence interval (CI) 0.38–0.77], p<0.001), with a 3-year EFS of 79.6% (95% CI 73.7–86.1) compared to pMMR patients (64.7% [95% CI 59.8–70.1]). For OS, there was no significant difference between the dMMR and pMMR cohorts (HR 0.73 [95% CI 0.47–1.16], p=0.181); however, within the small group of patients with an event, OS at 1 year for dMMR patients was 68.4% (95% CI 55.1–84.9) compared to 93.5% (95% CI 89.5–97.7) for pMMR patients (p=0.001).
Conclusions:
dMMR RC is rare, and tumour characteristics differ from those of patients with pMMR tumours (1). After controlling for clinical stage and age, this study suggests dMMR patients have improved EFS compared to pMMR patients. There is no significant difference in OS between groups but dMMR patients with an event have worse OS than pMMR patients, highlighting an additional need to prevent recurrence of disease within dMMR patients.1. Lunenberg, R et al. Poster presented at ESMO Congress (Presentation 569P), 13-17 Sept 2024, Barcelona, Spain.
Differential gut microbiota profiles among normal colorectal mucosa, adenomatous and hyperplastic polyps in healthy volunteers: ColoMAR-1 study.
Authors: Martos-Morillo Maria Dolores , Sanluis Idoia , Cardenas Jose M , Ulla Jose Luis , March Paula , Lopez Jorge , Ayuso Angel , Rodriguez-Pascual Jesus
Published: January 2025

271

Background:
Increasing evidence indicates that the interaction between intestinal microbiota and host cells plays an important role in colorectal cancer oncogenesis through immune, inflammatory and/or metabolic alterations. However, there are no clear evidence in the very early adenoma-carcinoma sequence at which microbiota species influences future steps to colorectal carcinoma. This study aims do find a point in the adenoma-carcinoma sequence ad witch microbiota species suggest the risk of a future tumor to develop less invasive forms of early diagnosis.
Methods:
In this cross-sectional study, healthy volunteers above 45 years old were selected to participate. Exclusion criteria includes previous colonoscopy performed in the last 5 years. Stool sample were collected before a colonoscopy with biopsy. Samples of normal mucosa were systematically obtained, and all polyps found were removed. In fecal samples, microbiota species were identified using GoodGut test:
Bacteroides fragilis, Subdoligranulm variabile, Ruminococcus, Roseburia, Coprococcus
, eubacteria,
Faecalibacterium prausnitzii
and
Gemella morbillorum
. Number of genomic copies/μL were analyzed using the Wilcoxon test.
Results:
From February to June 2024, 29 healthy volunteers between 45 and 69 years were recruited. 62% were female. Adenomatous polyps or hyperplastic polyps were found in 9 volunteers. No case of colorectal cancer was found. For species
S. variabile, Ruminococcus, Roseburia, Coprococcus
and
F. prausnitzii
, higher counts were found in stool samples from volunteers with adenomatous or hyperplastic polyps than in those from volunteer with a normal colonoscopy, both in the total count and after correction for bacterial load (p<0.001). For
B. fragilis
, bacterial count was higher in samples from volunteers with adenomatous polyps, but not in the samples from people with hyperplastic polyps compared with those samples from volunteers with a normal colonoscopy.
G. morbillorum
counts were not related to any type of polyps. None of this counts met the laboratory-designated threshold related to colorectal cancer.
Conclusions:
The presence of
B. fragilis
could be related to the differential risk of malignancy of adenomatous compared to hyperplastic polyps.

Bacterial count for each sample and specie.

Bacteria specie*
Normal mucosa
Adenoma
Hyperplastic

B. fragilis
22.13
22.3
20.42

S.variable
6.06
7.29
7.53

Ruminococcus, Roseburia, Coprococcus
6.08
7.29
7.47

F. prausnitzii
4.7
6.28
7.09

G.morbillorum
20.91
20.54
20.84

*Number of genomic copies/μL.
Role of
RAS/BRAF
and
PIK3CA
mutations in tissue and plasma for prognostic assessment in metastatic colorectal cancer (mCRC).
Authors: Terán-Brage Eduardo , Lopez-Mateos Yolanda , Abad Hernández María Mar , Sayagues-Manzano Jose Maria , Rodrigues Francoso Aline , Díaz-Sánchez Pablo , Fonseca-Sánchez Emilio , Vidal-Tocino Rosario
Published: January 2025

281

Background:
Mutations in
RAS/BRAF
(
RAS/BRAFm
) and
PIK3CA
(
PIK3CAm
) genes have been described as mechanisms of resistance to anti-EGFR agents in mCRC. However, the utility of liquid biopsy in their baseline detection remains unknown. We aim to analyse oncological outcomes according to
RAS/BRAF
and
PIK3CA
mutational status in tissue & plasma in mCRC.
Methods:
We conducted aretrospective study in patients (pts) with mCRC from 2017 to 2024.
RAS/BRAF
and
PIK3CA
mutational status assessment was performed at baseline using Idylla (Biocartis) and Cobas PIK3CA kits, respectively. Cox models were used to analyse overall survival (OS) in
RAS/BRAFm
and
PIK3CAm
vs wild-type (WT) population.
Results:
We analysed 404 paired samples (tissue & plasma) from 202p with mCRC.
RAS/BRAFm
was described in 45% (91p) in tissue and in 43.6% (88p) in plasma.
PIK3CA
was tested in 84p, with
PIK3CAm
detection in 19% (16p) in tissue and 11.9% (10p) in plasma. Liver involvement was more frequent in
RAS/BRAFm
vs WT (80.6% vs 63.9%; p=0.02), and in
PIK3CAm
vs WT population (94.4% vs 63.6%; p=0.01). Concordance study (tissue & plasma) for
RAS/BRAF
and
PIK3CA
are presented (Table). Subjects with concordant results had worse OS in
RAS/BRAFm
(18.1m vs 51.1m, HR=2.60; p<0.001) regardless of liver involvement, and showed the same trend in
PIK3CAm
(22.6m vs 28.1m, p=0.81). Patients with discordant results and plasma
RAS/BRAFm
or plasma
PIK3CAm
showed worse OS (23.7 m vs 51.1m; p = 0.006 and 16.4 m vs 42.5 m; p=0.18, respectively) and a lower disease control rate with anti-EGFR therapy (p = 0.04 and p=0.42, respectively).
PIK3CAm
were evenly distributed in
RAS/BRAF
WT vs mutated tumors (50% vs 51.5%; p=0.92) and had no independent prognostic impact in OS after stratifying by
RAS/BRAF
mutational status;
RAS/BRAF
WT (p=0,93) and
RAS/BRAFm
(p=0,91).
Conclusions:
Baseline determination of
RAS/BRAFm
and
PIK3CAm
by liquid biopsy in mCRC provide valuable prognostic and predictive information, extending its utility beyond tissue-based analysis.

Correlation study of
RAS/BRAF
and
PIK3CA
mutational status in tissue and plasma in mCRC.

RAS/BRAF
tissue

PIK3CA
tissue

RAS/BRAF

Plasma

Mutated
n (%)

WT
n (%)

Total
n (%)

PIK3CA

Plasma

Mutated
n (%)

WT
n (%)

Total
n (%)

Mutated n (%)
72 (80)
15 (13.4)
87 (43.1)

Mutated n (%)
7 (43.8)
2 (2.9)
9 (10.7)

WT n (%)
18 (20)
97 (86.6)
115 (56.9)
WT n (%)
9 (56.2)
66 (97.1)
75 (89.3)

Total n (%)
90 (100)
112 (100)
202 (100)
Total n (%)
16 (100)
68 (100)
84 (100)

Positive agreement: 72/90: 80%

Positive agreement: 7/16: 43.8%

Negative agreement: 97/112: 86.6%

Negative agreement: 66/68: 97.1%

Overall agreement: 169/202: 83.6%

Overall agreement: 73/84: 86.9%

KI*: 0.67

KI: 0.49

KI: Kappa Index.