bluuebunny/crossref_metadata_2025 huggingface dataset:
Determining MSI status by a one-step PCR melting curve analysis of Chinese-specific mononucleotide repeats.
Authors: Chen Huang , Jie Jianzheng , Jiang Ruiying , Wang Xiaowei , Wang Ye , Feng Qianqian , Niu Yun , Wang Bei , Luo Jie , Su Wenqing , Li Youcai , Gai Fei , Song Roman , Zhu Changbin , Zhong Dingrong
Published: June 2023

e15532

Background: Microsatellite instability (MSI) is a hypermutated phenotype primarily caused by the deficiency of DNA mismatch repair activity. Conventional MSI detection platforms are time consuming and need extra normal tissue. Due to the short DNA sequences of microsatellite loci in MSI samples, the method can be simplified to a one-step approach to differentiate MSI status by observing the melting curve. Herein a novel feasible MSI status detection method based on one step-PCR in single tumor tissue was developed, and validated in colorectal cancer samples. Methods: Specific microsatellite sites shorter than 12 bp in length (feasibility of fluorescence probes) were selected from public databases for analysis. In tumor tissues from 98 CRC patients with known MSI status, microsatellite sites with the highest receiver operating characteristic (ROC)-area under the ROC curve (AUC) were eventually selected for the final PCR panel design. The cut-off value of this assay was defined by the number of melting peaks in a specific Tm value range. An independent set of 199 tumor tissues from CRC patients with known MSI by Sanger sequencing was recruited to validate the performance of this novel PCR MSI kit. Results: The ROC-AUCs of the pre-selected eight mononucleotide repeats were 0.82, 0.93, 0.79, 0.78, 0.98, 0.95, 0.92, and 0.79. When 0 or 1 marker had a melting peak within the specified Tm value range, the sample was identified as "MSS/MSI-low (MSI-L)"; when 2 or more markers had melting peaks within the specified Tm value range, the sample was determined to be "MSI-high (MSI-H)". In the clinical sample set, compared with the results given by conventional MSI detection method, the sensitivity of the 8-gene panel for MSI-H was 99.4% (166/167), the specificity of the 8-gene panel was 100%, and the overall concordance reached to 99.5%. Conclusions: The novel PCR-MSI detection method using 8-gene panel developed in this study was feasible and accessible in clinical practice, and a large-scale clinical validation is in progress. [Table: see text]
High rates of detection of metastatic/recurrent colorectal cancer on clinical imaging at the time of molecular residual disease testing following operative management.
Authors: Trotier Danny , Lemmon Kayla , Golner Danielle , Buratti Maddie , DeZeeuw Alyssa , LoConte Noelle K. , Lubner Sam Joseph , Uboha Nataliya Volodymyrivna , Kratz Jeremy D. , Patel Monica Arun , Carchman Evie , Matkowskyj Kristina A. , Zhang Wei , Burkard Mark E. , Deming Dustin A.
Published: June 2023

e15543

Background: Detection of circulating tumor DNA (ctDNA) following operative management for colorectal cancer (CRC) as part of molecular residual disease (MRD) assays has shown significant prognostic implications. The majority of studies examining the time to detection of cancer recurrence have been done retrospectively without the treating physician knowing the results of the assay. Limited prospective data exists regarding the probability of detecting cancer on imaging at the time of a positive MRD test following operative management of all sites of disease. Here, we analyze the association of positive MRD testing with imaging findings of recurrent or metastatic CRC using a cohort of patients that underwent prospective MRD testing. Methods: Patients with stage I-IV intestinal cancers at University of Wisconsin Carbone Cancer Center who underwent prospective Natera Signatera MRD testing following operative management of their disease were identified and consented to an IRB-approved registry protocol. Those consented patients who had a positive test without being on systemic therapy and had clinical imaging within 45 days were analyzed further. The presence of definitive cancer, indeterminate findings, and no evidence of cancer was recorded per the treating physician using standard of care clinical imaging. The presence of cancer on imaging was then correlated with the quantity of ctDNA (mean tumor molecules (MTM)/ml). Results: 163 patients with stage I-IV CRC and 1 small intestinal cancer underwent MRD testing. 30 positive ctDNA tests with imaging were available across 22 unique patients (median age 54 years (29-84) 7 females). 23 samples were in the resected metastatic setting, 5 stage III and 2 stage I. Cancer was seen on imaging in 19/30 (63%) of positive tests, indeterminate in 3 (10%) and negative for cancer in 9/30 (27%). With ctDNA levels > 10 MTM/ml (n = 7), cancer was detected on imaging in all cases. With ctDNA levels of 1-10 MTM/ml cancer was detected in 42% and at < 1 MTM/ml in 64%. A trend towards greater detection of cancer was observed when MRI or PET/CT was performed. Radiologic disease detection in patients with positive MRD analysis was higher in those with stage IV disease (70%) vs. stage I-III (43%). Conclusions: ctDNA MRD positivity is associated with high rates of detection of recurrent/metastatic CRC, especially in patients with resected stage IV disease and with a quantity of > 10 MTM/ml. Clinical imaging should be considered at the time of detection of ctDNA.
Mutational and DNA fragment analysis may help in the triage of FIT+ patients enrolled in colorectal cancer screening programs.
Authors: Scimia Mauro , Pepe Francesco , Russo Gianluca , Malapelle Umberto , Tanaka Hiromi , Scimia Simone , Troncone Giancarlo , Bianco Maria Antonia
Published: June 2023

e15546

* F. Pepe made an equal contribution

Background: Mutational and DNA fragment analysis have already been investigated for a possible role in the detection of colorectal cancer. This pilot study, conducted at ASL NA 3 SUD (Naples, Italy) with the University of Naples Federico II, attempts to understand their possible role in the detection of Advanced Adenomas+ (AA+) and their potential ability to triage subjects with a positive FIT test for referral to colonoscopy. Methods: 160 FIT+ subjects of both genders, aged 50-74, participating in a colorectal cancer screening program were enrolled in a clinical trial focusing on a novel biomarker for colorectal cancer diagnostics. Of these, 14 subjects had disease (12 AAs and 2 colorectal cancers, from now on “CRC”). After ethical committee’s approval and release of informed consents, a 20 ml whole-blood sample was collected from each subject. Samples were centrifuged following standard procedures and stored at -80°C. DNA extraction was later performed using a Minielute kit (Qiagen). Mutational and DNA fragment analysis were performed using a qPCR-based technology: the ColoScape™ 2.5 kit (DiaCarta Inc, Pleasanton, CA). A logistic regression was run to determine the probability of disease in subjects showing positivity for predictors. Estimates of sensitivity, specificity, PPV, NPV (with 95% C.I.), PLR, NLR and Youden’s Index were also obtained. Results: The logistic regression showed statistical significance, with a p-value < 0.0001, that is, the logistic regression model with provides a better fit than the model without the independent variable. ColoScape identified 12 subjects with disease out of 14, for a sensitivity of 86% (67%,100%); both CRCs were picked up by ColoScape together with 10 AAs. 2 AAs were missed. Out of 146 healthy subjects, 107 were successfully identified as negatives, for a specificity of 73% (66%, 80%). PPV was 24% (12%, 35%). NPV was 98% (96%, 100%). PLR, NLR and Youden’s Index were 3.21, 0.19 and 0.59 respectively. Conclusions: This pilot study was intended to provide performance indicators to design a larger population study that is currently underway. These preliminary findings suggest that liquid biopsy-based mutational and DNA fragment analysis can play a role in selecting subjects with a higher risk of returning a positive colonoscopy, thus potentially improving the quality of colorectal cancer screening programs and patients’ experience.
Does severity of periodontal disease influence the risk of developing gastrointestinal malignancies?
Authors: Iqbal Umar , Mendes Duarte Poliana , Duncan William D. , Galochkina Zhanna , Zhang Zhongyue , Kostewicz Stephen H , Borobia Manuel E , Lee Ji-Hyun , Rogers Sherise C.
Published: June 2023

e15549

Background: In recent years, multiple observational studies have suggested increased risk of developing gastrointestinal (GI) malignancies in patients with prior periodontal disease (PD). Our aim was to determine whether a difference in incidence of GI malignancies exists amongst patients with pre-existing mild-moderate vs. severe PD. Methods: This was a single institution retrospective IRB approved study. We identified a cohort of patients between 2011-21 with PD and concurrent registration in independent dental and medical electronic health record systems at the University of Florida. Patients were stratified into 2 groups based on severity of PD (mild-moderate or severe). Descriptive statistics were used to compare the 2 groups based on demographics and medical history. Cumulative incidence curves were used to compare GI malignancy incidence between the 2 groups. Multivariable logistic regression was used to identify predictors of developing GI malignancies. Results: A total of 2168 patients with PD were identified with a median follow up of 4.7 (IQR 2.6-6.8) yr. Of these, 54% had severe PD and 46% had mild-moderate PD. Severe PD was more common within males (58% vs 50% in females), Black race (62% vs 52% in Caucasians), diabetics (59% vs 52% in non-diabetics), cigarette smokers (60% vs 51% in non-smokers) and excessive alcohol intake (70% vs 61% in moderate alcohol intake). There was no significant difference in cumulative incidence rates of GI malignancies (colon, pancreatic, gastric, hepatic, and esophageal) between the PD groups stratified by severity (12% in severe vs 11% in mild-moderate, p = 0.6 at 5 yr follow up). In univariable logistic regression, severe vs mild-moderate PD OR was 1.12 [95% CI: 0.87,1.46], thus more severe form of PD is not associated with developing a GI malignancy. In multivariable logistic regression, severe vs mild/moderate PD adjusted OR was 1.04 [95% CI: 0.79,1.36], thus also not statistically significant, with other risk factors of developing GI malignancies identified in Table 1. Conclusions: There was no association between the severity of periodontal disease and subsequent development of GI malignancy. [Table: see text]
Trends and disparities in incidence and mortality of early-onset colorectal cancer (EOCRC) in the United States (1999-2019).
Authors: Grewal Udhayvir Singh , Sohal Davendra
Published: June 2023

e15551

Background: There has been a startling rise in the reported incidence of colorectal cancer (CRC) among adolescents and young adults (AYA; ages 15-39 years) in the US.These patients are often diagnosed with advanced stage and have a relatively poor prognosis.Population-based data on disparities and trends in incidence and mortality in this understudied population are lacking. Methods: We used the Centers for Disease Control WONDER cancer statistics database to extract data on annual age-adjusted incidence (AAIR) and mortality (AAMR) rates per 100,000 population for colon and rectal cancer in AYA. We compared AYA statistics with the overall as well as the non-AYA population (40-85 years). Sex and race comparisons were analyzed. Variations in AAIR and AAMR over time, assessed with Joinpoint regression modelling (Joinpoint regression program 4.9.1.0), were expressed as estimated average annual percentage change (AAPC). Comparisons were reported using average annual percentage change difference (AAPCD). Results: 83,371 cases of EOCRC were reported between 1999-2019. We recorded an increase in AAIR of EOCRC (AAPC 2.9, p < 0.001). We noted a concomitant decline in AAIR of CRC overall (AAPC -2.4, P < 0.001) and among the non-AYA population (AAPC -2.4, p < 0.001). Subgroup comparisons showed statistically significant differences in AAIR of EOCRC for females vs males (AAPCD 0.6, p = 0.04), Whites vs Blacks (AAPCD 1.8, p < 0.001), and White females vs White males (AAPCD 0.6, p = 0.02) [table]. AAMR increased for EOCRC over the study period (AAPC 0.8, p = 0.001), as opposed to a decline in AAMR of CRC overall (AAPC -2.5, p < 0.001) and among the non-AYA population (AAPC -2.5, p < 0.001). The increase in AAMR of EOCRC was similar among males and females (AAPCD 0.3, p = 0.351), but higher among Whites vs Blacks (AAPCD 1.1, p = 0.007). Conclusions: This analysis from a large population-level database shows an increasing trend in incidence and mortality of EOCRC in the US, despite a concomitant decline in the incidence and mortality of CRC overall. The incidence appears to be rising more rapidly among females, particularly White females. Both incidence and mortality of EOCRC appear to be rising more rapidly among Whites compared with Blacks. Our analysis underscores the critical need to develop strategies to identify high-risk AYA populations who may benefit from more aggressive CRC screening and prevention interventions. [Table: see text]
Disparities in presentation, treatment, and overall survival for South Asian American patients with colorectal cancer.
Authors: Ahmed Kaleem Sohail , Marcinak Clayton Thomas , Krebsbach John K. , Schiefelbein Andrea M , Varley Patrick , LoConte Noelle K. , Zafar Syed Nabeel
Published: June 2023

e15554

Background: The South Asian population in America is growing. Colorectal Cancer (CRC) is one of the most common cancers amongst South Asian Americans (SAA), however few studies have looked at differential presentation, treatment, and outcomes. The objective of this study was to compare differences in presentations, and investigate disparities in treatment and overall survival (OS) amongst SAAs compared with non-Hispanic whites (NHW). Methods: We performed a retrospective analysis of patients with colon or rectal adenocarcinoma in the National Cancer Database (NCDB) years 2004-2020. We compared differences in patient demographics, socioeconomics, stage at presentation, and treatments received between SAA and NHW populations using chi square, and t tests as applicable. OS was evaluated using Kaplan-Meier analysis and the log-rank test. Multivariable Cox regression stratified by stage was used to compare OS between the two groups. Results: We analyzed data from 773,223 NHW and 3,448 SAA patients with colon cancer (CC) and 285,769 NHW and 1,826 SAA patients with RC. At presentation SAAs were younger (61.2 years vs 69.2 years, p<0.001 for CC, and 57.9 vs 63.9, p<0.001 for RC), less likely to have government insurance (44.1% vs 64.1%, p<0.001 for CC, and 35.4% vs 50.6%, p<0.001 for RC), more likely to be living in metropolitan areas (97.9% vs 83.2%, p<0.001 for CC, and 97.4% vs 81.0%, p<0.001 for RC), and more likely to have advanced stages of disease (47.4% vs 42.7%, p<0.001 for CC, and 40.9% vs 38.9%, p<0.001 for RC). SAAs had significantly longer delay in receipt of surgical intervention or radiation therapy (p <0.001) and were less likely to receive surgery for stage 4 for CC (54.6% vs 60.5%, p<0.001). On multivariate cox regression, adjusted for age, sex, insurance status, urban/rural location, and comorbid conditions, SAAs with either colon or rectal cancer were more likely to survive across all cancer stages (p<0.001). Conclusions: In this national study, when compared to NHW patients, SAA patients with CRC, present at younger ages and with more aggressive disease. Despite SAAs being less likely to receive timely cancer care, they have better overall survival. [Table: see text]
Real-world safety and effectiveness of MVASI in metastatic colorectal cancer patients in Canada.
Authors: Cheung Winson Y. , Samimi Setareh , Ma Kim , Knight Gregory John , Kassam Shaqil Nadirali , Colwell Bruce , Beaudoin Annie , Vincent Mark David , Trinkaus Mateya , Filion Alain , Karachiwala Hatim , Asmis Timothy , Sideris Lucas , Nunez Leyla , Wani Rajvi , Cirone Morris Carlye , Ngan Elaine , Du Yinhao , Inam Naila
Published: June 2023

e15555

Background: MVASI is a biosimilar to the reference product, bevacizumab, and is the first biosimilar approved by Health Canada for the first-line (1L) treatment of metastatic colorectal cancer (mCRC). This study addresses the limited real-world evidence by describing the safety and effectiveness of MVASI as 1L therapy in mCRC. Methods: Retrospective data were collected in two waves of sites across Canada, at least 1 year (wave 1) or 2 years (wave 2) after commercial availability of MVASI at each site. Adult patients treated with ≥ 1 MVASI cycles as their 1L therapy for mCRC were included. Baseline demographic and clinical characteristics were collected 6 months prior to MVASI initiation (index date). Medical history, adjuvant treatment, and CRC diagnosis were collected within 5 years of pre-index date. Outcomes were gathered between index and chart review dates. Results: Among the 75 patients in wave 1, 36 (48.0%) were male and the median age was 62 years. Of the 164 patients in wave 2, 98 (59.8%) were male and the median age was 67 years. Most patients in wave 1 (42/69; 60.9%) and wave 2 (87/141; 61.7%) had a RAS mutation. The median time from mCRC diagnosis to MVASI initiation among wave 1 and 2 patients was 3.1 (IQR [2.1, 4.2]) and 2.3 months (IQR [1.6, 3.7]), respectively. At least one safety event of interest (EOI) was recorded for 26/75 (34.7%) wave 1 and 70/164 (42.7%) wave 2 patients (Table 1). The median progression free survival (PFS) for wave 1 and 2 patients were 9.47 and 21.38 months, respectively. Median overall survival (OS) for wave 1 patients was not estimable and was 26.45 months for wave 2 patients. Conclusions: In this real-world study, mCRC patients treated with 1L MVASI were generally representative of the Canadian mCRC population treated with 1L bevacizumab. Compared with clinical trials of MVASI and reference bevacizumab, the EOI profile and the OS data are similar, but lower rates of individual EOIs are observed in this real-world setting. The shorter PFS observed in wave 1 may be due to higher rates of comorbidities at baseline and longer time from mCRC diagnosis to index. [Table: see text]
Efficacy and safety of radiation therapy combined with anti-angiogenic agentsand immunotherapy for MSS/pMMR metastatic colorectal cancer: A real-world study.
Authors: Lin Zhenyu , Zhai Menglan , Zhang Tao
Published: June 2023

e15559

Background: The combination of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs) can reshape tumor microenvironment, and their effectiveness has been demonstrated in pattients with microsatellite stable (MSS) or mismatch repair profificient (pMMR) metastatic colorectal cancer (mCRC). Radiotherapy (RT) can induce tumor immunogenic cell death, increase infiltration of tumor-infiltrating T lymphocytes and enhance neoantigen expression. Whether the application of RT can further improve the prognosis of pts with MSS/pMMR mCRC receiving anti-vascular drugs and immunotherapy remains to be explored. Methods: We retrospectively identified data on mCRC pts who received anti-angiogenic targeted agents and ICIs after failure of standard therapy at our institution from January 2015 to September 2022. Pts either received RT (RT+TT+IT group) or did not (TT+IT group) during the course of the disease. Baseline characteristics of the groups were compared with the Chi-squared, Fisher's exact, or the independent sample t-test as appropriate. Progression-free survival (PFS) and overall survival (OS) were examined by the Kaplan-Meier method with a log-rank test. Univariate and multivariate Cox regression analysis was conducted to identify prognostic factors for PFS and OS. Results: Of the 89 pts who received anti-angiogenic targeted therapy in combination with ICIs, 43 (48.3%) received RT and 46 (51.7%) did not. All pts were MSS/pMMR. The objective response rate (ORR) of the RT+TT+IT and TT+IT groups was 18.6% (8/43) and 10.9% (5/46) and the disease control rate (DCR) was 83.7% (36/43) and 67.4% (31/46) (both p > 0.05), respectively. The median PFS time was slightly higher in the RT+TT+IT group than in the TT+IT group (5.0 vs. 4.3 months, p = 0.065). In addition, the PFS of RT sequential/simultaneous TT+IT was superior to TT+IT sequential radiotherapy (RT→IT+TT vs. RT-IT+TT vs. IT+TT→RT: median 7.5 vs. 6.1 v.s 3.8 months, p = 0.004). The median OS of RT+TT+IT group was significantly better than that of TT+IT group (15.2 vs. 7.2 months, p = 0.026). Application of RT appeared to be most benefificial in pts aged 56 or younger, advanced stage of initial diagnosis, metastatic lesions involving ≥2 organs, primary lesion not resected, RAS mutations. Cox multivariate regression analysis showed that the number of anti-angiogenic agents plus ICIs cycles > 4 was an independent prognostic factor for OS. No treatment-related deaths were reported, and radiation pneumonia occurred in one patient in the combined radiotherapy group in a manageable manner. Conclusions: The addition of RT during the course of disease can significantly improve the survival benefit of MSS/pMMR mCRC pts treated with anti-angiogenic drugs combined with ICIs posterior line therapy.
Efficacy and safety of trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil monotherapy for refractory metastatic colorectal cancer: A retrospective study.
Authors: Li Rongrong , Zhou Hui-Jun , Zeng De-Yu , Jiang Shao-Feng , Liu Wu , Liu Zhen-yang
Published: June 2023

e15562

Background: There had been no phase III trial to compare the efficacy between trifluridine/tipiracil (TAS-102) plus bevacizumab (BEV) with TAS-102 monotherapy in refractory metastatic colorectal cancer (mCRC). Our study sought to investigate the efficacy and safety of TAS-102 plus BEV versus TAS-102 monotherapy in these patients. Methods: We retrospectively analyzed the patients with refractory mCRC who received TAS-102 (35 mg/m2 twice daily; day 1–5 and 8–12; every 28 days) with or without BEV (5 mg/kg; day 1,15; every 28 days) between November 2020 and October 2022 in Hunan Cancer Hospital. All patients had previously received at least second-line treatment. The primary endpoint was overall survival (OS). Results: A total of 58 patients received TAS-102 plus BEV, and another 32 patients received TAS-102 monotherapy. With a median follow-up of 4.60 months (range, 0.20–22.80), the median overall survival (mOS) was 10.83 months [95% confidence interval (CI), 10.10–NA] for TAS-102 plus BEV, 7.43months (95% CI, 5.17–NA) for TAS-102 monotherapy. The hazard ratio (HR) was 0.90 (95% CI, 0.42–1.92), P= 0.78. Median progression-free survival (mPFS) was 4.67 months (95% CI, 3.57–7.37) for TAS-102 plus BEV, and 4.30 months (95% CI, 3.03–NA) for TAS-102 monotherapy. The HR was 1.04 (95% CI, 0.54–1.99), P= 0.91. The Cox multivariate regression analysis demonstrated that the patients who received treatment after TAS-102 with or without BEV(HR:0.25;95% CI, 0.09-0.71) and previously undergone Irinotecan (HR:0.23;95% CI, 0.06-0.95) were independent risk factors for OS and the patients who previously received Cetuximab was confirmed to have a significant better PFS(HR:0.17;95% CI, 0.03-0.91). Of the 70 patients who were evaluated, the TAS-102 plus BEV showed higher ORR and DCR than TAS-102 monotherapy, but the difference was not significant (ORR: 12.2% versus 0%; p= 0.16; and DCR: 77.5% versus 61.9%; p= 0.29). The incidence of platelet count decrease (grade ≥3) was significantly higher in the TAS-102 plus BEV group than the TAS-102 monotherapy group (3.00% vs. 0.00%, p = 0.03), whereas other adverse events were comparable between the two groups. Conclusions: Compared with TAS-102 monotherapy, TAS-102 plus BEV seemed to have comparable safety but improved disease control and prognosis in patients with refractory mCRC, although the difference was not significant. Further prospective studies are still needed to confirm our conclusions. [Table: see text]
Phase II of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.
Authors: Fumet Jean-David , Bertaut Aurelie , Roussot Nicolas , Bellio Hélène , Bengrine-Lefevre Leila , Vincent Julie , Niogret Julie , Palmier Rémi , Collot Thomas , Rambach Laurie , Boudrant Axelle , Parnalland Sophie , Rederstorff Emilie , Hennequin Audrey , Zanetta Sylvie , Hervieu Alice , Ghiringhelli François
Published: June 2023

e15563

Background: In chemorefractory metastatic colorectal cancer (mCRC), targeted therapy such as TAS-102 and regorafenib have shown a modest survival benefit with a median progression free survival (PFS) of only about 2 months. A phase I of FOLFIRINOX3-bevacizumab (bFOLFIRINOX 3) defined the RP2D for irinotecan and showed promising activity. The aim of this phase II trial was to evaluate the safety and efficacy of bFOLFIRINOX-3 in chemorefractory mCRC. Methods: The phase I trial defined the combination of bFOLFIRINOX-3 at the irinotecan’s RP2D of 70mg/m² day 1 and day 3. In phase II, patients > 18years and ECOG 0 or 1, with a pathological confirmed mCRC and experienced treatment failure after standard chemotherapies that include at least 5-fluorouracil, oxaliplatin and irinotecan were enrolled. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg), folinic acid (400mg/m2), 5-fluorouracil (2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (70mg/m² administered before and after infusional 5-fluorouracil). CT scan were performed every 2 months. Primary endpoint was the 2-months PFS. Secondary endpoints included objective response rate (ORR), median PFS, overall survival (OS) and toxicity. Results: Twenty-free patients were enrolled (October 2018 to December 2022). Median age was 62 y (range: 50-70y). These patients have been treated with several previous lines of chemotherapy (median = 3, range [1-6]). Median follow up was 11 months (range [3-31.3]). The 2-months PFS was 100%. Overall response rate was 17,4%. Median PFS was 7.8 months (IC95%[5.9;9.5]) and median OS was 31.3 months (IC95% [12.4;NR]). Grade 3 adverse events occured in 43.5% with mostly diarrhea (39.1%) and neutropenia (21.7%). Grade 3 diarrhea was consistently resolving after a dose reduction of chemotherapy. The most common drug-related adverse events (all grades) were fatigue (60.9%), diarrhea (73.9%), nausea (39.1%), peripheral neuropathy (47.8%), thrombopenia (82.6%) and anemia (56.5%). Conclusions: The combination of bFOLFIRINOX-3 yielded better ORR, median PFS and OS than standard of care. The regimen was well tolerated. The study met its primary endpoint and support for future randomized phase III compared to standard of care. Clinical trial information: NCT03795311 .
Clinical and molecular characterization of HER2-low metastatic colorectal cancer.
Authors: Babkoff Aryeh , Keidar Haran Tal , Zick Aviad , Hubert Ayala , Grinshpun Albert
Published: June 2023

e15573

Background: HER2 is a well-established biomarker and target in multiple tumor types, including metastatic colorectal cancer (mCRC). Despite the lack of HER2 amplification, certain HER2-low tumors were recently found to respond to novel HER2-directed antibody-drug conjugates, warranting an exploration of the clinical and molecular features of these entities. Yet, the real-world prevalence and the clinicopathologic characteristics of HER2-low mCRC are largely unknown. Here, we aim to describe the features of HER2-low mCRC and compare them to HER2-0 colorectal tumors. Methods: We retrospectively reviewed clinicopathologic data from consecutive patients with mCRC undergoing HER2 testing (immunohistochemistry [IHC] and in-situ hybridization [ISH], when appropriate) between 2017 and 2021 at Hadassah Medical Center, Israel. Tumors were defined HER2-positive (HER2+) if scored IHC 3 + or IHC 2+/ISH positive; HER2-low if scored IHC 2+/ISH negative or IHC 1+; HER2-0 if scored IHC 0. Genomic alterations were determined through a targeted next-generation sequencing (NGS) panel. Clinicopathologic and genomic data were compared between the cohorts with the Mann-Whitney or Fisher's exact test, and survival using Log-rank test. Results: A total of 100 consecutive mCRC patients were found eligible for our study, including 4 (4%) with HER2+, 30 (30%) with HER2-low, and 66 (66%) with HER2-0 disease. In the HER2-low group, five tumors were HER2 +2 / ISH negative, and 25 were scored HER2 +1. The fraction of female patients was 40% in HER2-low group, and 42% in the HER2-0 cohort (p > 0.99). The prevalence of mismatch repair deficient (MMR-D) tumors was also similar, with one MMR-D tumor in the HER2-low group, compared to 3 tumors in the HER2-0 (p > 0.99). 60% of the primary tumors in both groups originated in the left colon and rectum. Also, the prevalence of mucinous histology was comparable between the HER2-low and the HER2-neg cohorts (7.4% vs. 4.8%, p = 0.64). Among patients receiving local somatic NGS testing (n = 61), the fractions of patients with KRAS, BRAF, and TP53 mutations were largely comparable between the cohorts (Table 1). With a median follow up of 37 months, the median overall survival was 41 months for the HER2-low group and 51 months for the HER2-neg group (p = 0.15). Conclusions: In our cohort of patients with HER2-negative mCRC, the clinicopathologic and genomic characteristics of HER2-low and HER2-0 tumors did not differ significantly. However, our data suggest that HER2-low tumors represent a significant portion of mCRC, supporting further development of novel HER2-directed therapies for this population. Additionally, our data also support the notion that HER2-low, as currently defined, is not a distinct molecular subtype of mCRC. [Table: see text]
Refractory colorectal cancer patient derived MicroOrganoSpheres (MOS) to enable correlation of targeted therapy combination response with clinical outcomes.
Authors: Ding Shengli , Kanikarla Marie Preeti , Baro Nicholas , Raman Renuka , Helman Elena , Hsu Shiaowen David , Kopetz Scott , Shen Xiling
Published: June 2023

e15574

Background: Metastatic colorectal cancer (CRC) patients who have become resistant to standard-of-care (SOC) treatments are often put on targeted therapies, including experimental drugs still in clinical trials. However, patients with targeted mutations still often do not respond to the targeted therapies alone, hence it remains a critically unmet need to explore potential combinatorial regimens that will enhance the efficacy. Methods: We performed a high-throughput screen using MicroOrganoSpheres (MOS) derived from metastatic refractory patients to correlate with clinical outcomes and explore alternative combinations that might benefit the patients. Biopsies from metastatic CRC patients who became resistant to SOC and were about to receive targeted therapies in clinical trials were molecularly profiled and implanted into immunodeficient mice to generate patient-derived xenografts (PDX). Results: MOS were derived and established from PDX using droplet-based microfluidics for high-throughput 3D screening. These MOS-based refractory patient avatars contain either targetable mutations including KRAS G12C and BRAF 600E or no such mutations. Response of the MOS to dose-titrated single and combination drug treatments including the available targeted therapies were measured by a fully automated robotic dispensing and imaging pipeline and quantified by AI-based live imaging analytical algorithm to generate robust drug response curves, which were used to derive IC50 and EC50. We tested both FDA-approved and experimental targeted therapies as single agent or in combination in 5-dose titrations. Longitudinal tracking of each MOS with Live/dead fluorescence dye signals was obtained for 5 days. MOS drug response curves and IC50s show correlation with clinical outcomes. This comprehensive dataset enabled us to assess the potential benefit of different combinations, help deconvolute the efficacy and synergy of individual drugs, and provide insight into patients who fail to response to targeted therapies despite possessing the targeted mutations. As the MOS diagnostic assay can be completed from a patient biopsy within 10 days and is currently in a registered, multi-site clinical trial (ClinicalTrials.gov # NCT05189171), this study provides proof-of-principle for a potential clinical MOS-based assay to guide refractory patients to the optimal combination regimen containing targeted therapy. Conclusions: Refractory patients may benefit from a MOS-based high-throughput screen assay to select the optimal combination regimen containing targeted therapy.
The preventive effect of celecoxib on regorafenib-associated hand-foot syndrome in patients with liver metastasis from colorectal cancer: A single-center, retrospective, real-world study.
Authors: Wang Lijun , Wang Hongwei , Liu Wei , Jin Kemin , Bao Quan , Wang Kun , Xing Baocai
Published: June 2023

e15576

Background: Regorafenib, an oral multi-kinase inhibitor, is the third- or later-line therapy for colorectal cancer with liver metastasis (CRLM), but the hand-foot syndrome (HFS) is its most common adverse reaction. Celecoxib, a selective COX-2 inhibitor, can treat inflammation. This study aimed to explore whether additing celecoxib to the cancer therapy regorafenib can prevent or alleviate the HFS, improve drug tolerance, and prolong the patient’s survival. Methods: In the retrospective cohort analysis, patients with colorectal cancer and liver metastasis, to whom regorafenib and celecoxib were administered in the Department of Hepatopancreatobiliary Surgery of Beijing Cancer Hospital between November 2021 and October 2022, were included. Upon the medical records from physical examination and other means of follow-ups, the Kaplan-Meier estimator analyzed the survival function and the severity of adverse events was described according to the CTCAE v.5.0 standards. Results: Twenty-six patients were included in the analysis and 14 colorectal cancer patients had extrahepatic metastases at the onset of the treatment. All patients received regorafenib and celecoxib. Further, 15 patients were treated with a combination of immune checkpoint inhibitors, 3 patients underwent combined local-regional therapy, 1 patient received combined chemotherapy, and 7 patients received regorafenib. Among all the patients, the incidence of grades 1 & 2 HFS was 46% and no grade 3 HFS was observed. The other main adverse events were hoarseness (35%), fatigue (27%), rash (27%), and neutropenia (15%). The most frequent adverse events from the CONCUR study and current analysis are shown in Table 1. Five patients (19%) had their treatment interrupted or their drug dose reduced due to adverse events. The median follow-up time of all patients was 5.3 (range, 1.6-13.1) months, the overall survival was not reached, and the median progression free survival was 2.9 (95% CI: 1.5-4.3) months. As the overall response in all patients after treatment, 3 cases (12%) achieved PR, 11 cases (42%) had SD and 12 cases (46%) showed PD. Conclusions: The addition of celecoxib to the cancer-line therapy regorafenib in CRLM patients did not reduce the incidence of HFS, but reduced the severity of HFS (grade 3). Also, it did not shorten the survival time of the patients. The addition of celecoxib to the main therapy might alleviate some adverse effects. [Table: see text]
Predictors of response in advanced colorectal cancer (CRC) patients treated with immune-checkpoint inhibitors (ICI).
Authors: Benson Katherine K , Paul Samuel , Min Eric , Xu Menglin , Noonan Anne M. , Mittra Arjun , Malalur Pannaga G. , Roychowdhury Sameek , Jin Ning , Hays John L. , Elkhatib Rifat T. , Rahman Shafia , Miller Eric David , Diaz Pardo Dayssy Alexandra , Manne Ashish
Published: June 2023

e15579

Background: ICI is reserved for mismatch repair (MMR) deficient and high tumor mutation burden (TMB) CRC patients in the current clinical practice. Identifying clinicopathological factors predicting response to ICI beyond MMR status could help effectively utilize ICI in this population. This is a retrospective review of advanced CRC (recurrent or metastatic) patients treated with ICI at an academic institute to identify the risk factors (RF) for poor outcomes. Methods: CRC patients who received at least one dose of ICI for between 1/1/2015 and 7/31/2021 at the Ohio State University were included in the study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse events (irAE) details and survival outcomes. Descriptive statistics were used, Fisher exact test to compare categorical variables, log-rank test rank test for survival outcomes, and logistic regression model for categorical outcomes using JMP Pro 16 (SAS Institute Inc., Cary, NC). Results: Our cohort has 46 advanced patients (37 colon and 7 rectal), the median age was 51 years (range 26-82) with 52% females, 95% Caucasians, 76% had metastatic disease (47% and 32% had liver and lung metastases or mets, respectively), 41% were mismatch repair (MMR) deficient, and 30% had KRAS exon two mutations. About 30% and 43% got ICI in the first line and ≥ 4 lines, respectively. Most patients received pembrolizumab (57%), followed by nivolumab (28%), atezolizumab (11%), and durvalumab (4%). Chemotherapy and ICI combination was given in 39%. irAEs were reported in 19% (n = 9). Median overall survival (OS) and progression-free survival (PFS) were 37 months (m) (95% confidence interval [CI], 14-NR) and 15m (95% CI, 7-35), respectively. Baseline (before the first ICI dose) albumin (p = 0.005), hemoglobin or Hb (p = 0.001), and the red cell count or RBC (p = 0.003) were negatively related to OS, while platelet to lymphocyte ratio or PLR (p = 0.01) and alkaline phosphatase levels (p = 0.03) were positively related to OS. High BL white cell count (WBC) (p = 0.04), alkaline phosphatase or ALP (p = 0.01), and low albumin (p = 0.002) and alanine transferase or ALT (p = 0.005) significantly impacted the OS. Other significant predictors are discussed in the table below. Conclusions: Our study provides insights into baseline tumor characteristics (such as lung/liver mets, KRAS exon 2 mutations, and MMR status) and lab values (such as RBC, Hb, PLR, albumin, ALP, and ALT) that could predict tumor response in CRC patients treated with ICI. These associations must be validated in larger studies. [Table: see text]
Resection of primary colon cancer with and without resection of liver metastases: Propensity-score matched analysis.
Authors: Emile Sameh Hany , Horesh Nir , Garoufalia Zoe , Gefen Rachel , Zhou Peige , Wexner Steven D
Published: June 2023

e15580

Background: Studies show that attempts to treat liver metastases during or before primary colonic cancer resection may improve survival. We aimed to compare overall survival of patients with colon cancer and liver metastases who underwent primary tumor resection with/without resection of liver metastases. Methods: This retrospective cohort study included patients with stage IV colon adenocarcinoma and isolated liver metastases who underwent surgical resection, using data from the National Cancer Database between 2015-2019. Patients with metastases to other organs or who did not have primary tumor resection were excluded. The cohort was divided into Colectomy-only (resection of primary colonic cancer only) and Colectomy-plus (resection of primary tumor and liver metastases) groups. After comparing, significant baseline and treatment confounders were identified and groups were matched using the nearest neighbor, 1:1 propensity-score method. Primary outcome was overall survival; secondary endpoints were short-term mortality and 30-day unplanned readmission. Results: 6780 patients who underwent primary tumor only resection and 4082 who underwent primary tumor and liver metastases resection were included. Patients in the Colectomy-only group were significantly older (63.73±13.59 vs 59.56±13.32 years;p < 0.001), more often male (56% vs 53.5%;p = 0.01), had more comorbidities (Charlson score 3: 4.4% vs 3.3%;p = 0.001) and right-sided colonic cancer (45.7% vs 43.2%;p = 0.002), shorter time before surgery (10 vs 30 days;p < 0.001), and more laparoscopic surgery (40.4% vs 35%;p < 0.001). Colectomy-only group patients had less chemotherapy (48.6% vs 50.7%, p = 0.04) and immunotherapy (34.1% vs 40.6%, p < 0.001) whereas Colectomy-plus group patients had more neoadjuvant systemic therapy (18.8% vs 10.2%;p < 0.001). Median overall survival of the Colectomy-plus group was significantly longer than Colectomy-only group (45.1 vs 24.4 months; p < 0.001). After matching for significant confounders, 2038 patients were included in each group. There were no significant differences between the two groups in 30-day (3.8% vs 3.1%;p = 0.3) and 90-day mortality (7.7% vs 6.6%;p = 0.2). Colectomy-plus group patients had significantly higher 30-day unplanned readmissions (7.2% vs 5.3%, p = 0.02) and significantly longer median overall survival (41.5 vs 28.4 months, p < 0.001). On Cox-regression analysis, resection of liver metastases and primary colonic tumor was associated with 33% mortality reduction (HR: 0.678, 95%CI: 0.618-0.745, p < 0.001). Conclusions: Resection of colonic cancer liver metastasis with the primary tumor is associated with significant survival benefit and may prolong survival by approximately 12 months, versus primary tumor resection alone. Synchronous resection of the primary tumor and liver metastases should be considered as it appears to offer survival benefit.
Safety and effectiveness of subtotal pelvic peritonectomy for patients with colorectal cancer with limited peritoneal metastasis in pelvic cavity.
Authors: Liao Leen , Tang Jinghua , Xiao Binyi , Jiang Wu , Han Kai , Kong Ling-Heng , Yu Jiehai , Pan Zhi-Zhong , Ding Pei-Rong
Published: June 2023

e15587

Background: Cytoreductive surgery with extensive visceral resection and peritonectomy has shown long-term survival benefits for colorectal cancer (CRC) patients with peritoneal metastasis. However, the extent of peritonectomy remains controversial for limited peritoneal metastasis. This study modified the selective pelvic peritonectomy (SPP) to subtotal pelvic peritonectomy (STPP) for patients with limited peritoneal metastasis in pelvic cavity, and aimed to assess the outcome of STPP. Methods: CRC patients with limited peritoneal metastases in pelvic cavity and underwent R0 resection were included from a prospectively collected database. Grade III/IV morbidity rate, disease free survival (DFS) and overall survival (OS) were analyzed. Results: A total of 51 patients were included (22 in the STPP group and 29 in the SPP group). An average of 60 minutes increased in operative time in the STPP group, but no perioperative mortality occurred. Grade III/IV complication rates did not differ between two groups. At a median follow-up of 38.1 months, the 3-year-DFS was 63.0% in the STPP group and 29.3% in the SPP group ( P = 0.006). The 3-year-OS was 82.6% and 55.6% for the STPP and SPP groups, respectively ( P = 0.033). Moreover, STPP was independently associated with improved DFS. Eight (38.1%) cases with remaining ovaries developed ovarian metastasis, of whom 6 (75%) underwent a second operation. Conclusions: Subtotal pelvic peritonectomy is associated with promising long-term outcome in CRC patients with limited peritoneal metastasis in the pelvic cavity. Prophylactic bilateral oophorectomy should be strongly considered during this procedure.
Proteomic profiling of FOLFOX-resistant colorectal cancer cells.
Authors: Tam Shing Yau , Islam Khan Md Zahirul , Yip Jerica Hiu Yui , Yan Hong Yiu , Tam Tsz Yan , Law Helen Ka Wai
Published: June 2023

e15588

Background: Chemoresistance is a major cause of colorectal cancer (CRC) mortality. Although multidrug regimen has been established as the backbone of CRC chemotherapy for better treatment efficacy, chemoresistance is common among late-stage CRC. Proteomic profiling of both the chemoresistant and wild-type CRC cells may provide hints for the mechanisms of chemoresistance and suggest targets for improving chemotherapy efficacy. Methods: Human CRC cell lines (DLD-1 and HCT-116) were treated with progressively increased dosage of FOLFOX (5-flurouracil (5-FU), folinic acid (LEU) and oxaliplatin (OXA)) to develop chemoresistance as DLD-1-R and HCT-116-R respectively. After confirmation of the successful development of chemoresistance by Cell Counting Kit-8 test (CCK-8), the comparison of cell samples between chemoresistant and wild-type cell lines were conducted by proteomic profiling using quantitative mass spectrometry (MS)-based techniques. MS and MS/ MS peptides spectra were analysed by Progenesis QI for proteomics software compared with Swiss-Prot dataset. Differentially expressed proteins (DEP) are defined as -1 > log2FC > 1, p < 0.05. Gene-list enrichment by Enrichr (https://maayanlab.cloud/Enrichr/) was employed for identifying the hallmark gene sets of the significantly enriched molecular processes and pathways of each group. All experiments were performed with at least 3 replications. Results: The development of FOLFOX-resistance took one year. The highest drug concentrations achieved were 0.5mM 5-FU, 50µM LEU, and 50µM OXA for DLD-1-R, and 5µM 5-FU, 0.5µM LEU, and 0.5µM OXA for HCT-116-R. The chemoresistance was found to be 14.73 (DLD-1-R) and 1.61 (HCT-116-R) times of the wild-type DLD-1 and HCT-116 respectively from CCK-8 tests. A total of 345 DEP with 154 up-regulated and 191 down-regulated proteins were found in DLD-1-R. While a total of 95 DEP with 66 up-regulated and 29 down-regulated proteins were found in HCT-116-R. Gene ontology molecular process (2021) analyses found that cadherin binding were significantly enriched in both DLD-1-R and HCT-116-R (Adjusted p-value < 0.05). KEGG pathway (2021) analysis found that oxidative phosphorylation, regulation of actin cytoskeleton and HIF-1 signalling pathway are among the significantly enriched pathways in DLD-1-R (Adjusted p value < 0.05). There was no significantly enriched pathway found in HCT-116-R in the same analysis. Conclusions: Our study has successfully established CRC cells with chemoresistance to the FOLFOX regimen. Proteomic profiling has found the cadherin binding as the significantly altered molecular process along with several important signalling pathways in chemoresistant CRC cells. These findings could suggest new directions in the development of anti-chemoresistance strategies of CRC.