tbuckley/cabot-search huggingface dataset:
Clonal hematopoiesis of indeterminate potential (CHIP): Outcomes and adverse events in patients with solid tumors.
Authors: Tharani Krishnan, Joao Paulo Solar Vasconcelos, Emma Titmuss, James T. Topham, Robert Vanner, David F. Schaeffer, Aly Karsan, Howard J Lim, Cheryl Ho, Carl J. Brown, Sharlene Gill, Hagen Fritz Kennecke, Derek J. Jonker, Eric Xueyu Chen, Daniel John Renouf, Christopher J. O'Callaghan, Jonathan M. Loree
Journal: Journal of Clinical Oncology (2024)

3521 Background: CHIP is the clonal expansion of hematopoietic stem cells following acquisition of somatic mutations. It is a common incidental finding in cell-free DNA (cfDNA). We investigated the incidence of CHIP in cfDNA from patients with solid tumors and explored its association with outcomes and adverse events (AEs). Methods: We reviewed cfDNA results from a local prospective solid tumor cohort (PREDICT-L) and two randomized trials: CCTG CO.26 (durvalumab + tremelimumab [D+T] or best supportive care [BSC] in metastatic colorectal cancer [mCRC]) and CCTG PA.7 (gemcitabine and nab-paclitaxel [GN] +/- D+T in metastatic pancreatic adenocarcinoma [mPDAC]). CHIP+ was defined as any mutation in DNMT3A, TET2, ASXL1or ATM with a variant allele frequency (VAF) 2% or higher. Variants were considered germline if the VAF was &gt;40%, or were annotated as germline by respective assays. The first line of treatment after cfDNA was reviewed for grade 3 or higher and dose-limiting AEs. Results: The prevalence of CHIP was 10%-21% and was more common in older patients (p=0.003). There was no association between CHIP and sex (p=0.80) or ECOG status (p=0.31). The VAF of CHIP variants was similar across all panels, and DNMT3A was the gene most frequently mutated in all cohorts. Patients with CHIP in PA.7 treated with immunotherapy (IO) had improved progression-free survival (PFS) versus patients without CHIP (p=0.036, p-interaction=0.061 [multivariable]). However, patients with CHIP treated with chemotherapy (Chemo) showed a trend towards worse overall survival (OS) in the PREDICT-L cohort (p=0.057). There was no significant difference in the rates of AEs between the CHIP+ versus CHIP- groups for those treated with Chemo or IO. Conclusions: CHIP is common in patients with solid tumors. Although not appearing to impact rates of AEs, CHIP may impact outcomes from Chemo or IO. [Table: see text]
Mortality outcomes in early versus late onset colorectal cancer: A US National Inpatient Sample (NIS) analysis (2020).
Authors: Muhammad Atif Khan, Shahryar Khan, Muhammad Kashif Amin, Faiza Humayun Khan, Mashal Alam Khan, Samia Asif
Journal: Journal of Clinical Oncology (2024)

e15651 Background: Colorectal Cancer (CRC) is the third most common cancer diagnosed in the United States and contributes to significant cancer-related morbidity and mortality. An upward trend in the incidence is noticed in the population below 50 years of age. For similar reasons, U.S. Preventive Services Task Force recommended screening at the age of 45 in 2021.For the sake of this study, we categorized early onset (EO) for age 45 and below, and late onset (LO) for above 45 years per new screening criteria. We compared socioeconomic characteristics, mortality, length of stay and hospital cost between EO and LO CRC. Methods: It is a retrospective cohort study of adult patients hospitalized in 2020 with Colorectal cancer in acute care hospitals across the USA. Patients were selected from the Nationwide Inpatient Sample (NIS) database. IRB approval was not obtained as de-identified data was utilized. Our study population included all patients with a discharge diagnosis of colorectal cancer as their primary diagnosis using the International Classification of the Diseases (ICD-10). The primary outcome was in-hospital mortality, secondary outcomes were length of hospital stay and total hospitalization charges. Analysis was performed using STATA version 18.0. Univariable and Multivariable logistic regression analysis were used to adjust for potential confounders. Results: There were 32 million discharges included in the NIS database in 2020, our study included 153809 with colorectal cancer which includes 12043 in EO and 141750 in LO CRC. Both population groups are mostly similar in terms of baseline characteristics, however EO group were more likely to have Hispanic population (18.7% vs 9.5%), history of inflammatory bowel disease (2.9% vs 1.2%), family history of CRC (6.4% vs 3.8%) and smoker (15.8% vs 12.8%). Multivariable analysis revealed that Age, Sex, Charlson Comorbidity Index, Family history, Smoking, and Median household income for patients were predictors of mortality. There was no statistically significant difference found in the adjusted mortality between the two groups (odds ratio 1.08, 95% CI 0.84-1.39). Lower length of stay was noticed in the EO group (odds ratio 0.48, 95% CI 0.07-0.89). Total deaths are lower in EO than LO group (0.04% vs 0.06%). Conclusions: There is no difference in mortality in early and late onset CRC in our study. However, EO CRC is associated with shorter length of stay in hospital. EO CRC disproportionately affects non-White patients, particularly Hispanic patients. [Table: see text]
PIPAC in patients with peritoneal metastases from gastrointestinal tract (PIPOX): An open label, non-comparative phase 1/2 dose escalation and expansion trial.
Authors: Frederic Dumont, Vahan Kepenekian, Christophe Passot, Anne-Cecile Ezanno-Manasterki, Marc Pocard, Jean-Luc Raoul, Benedicte Lelievre, Sandrine Hiret, Hélène Senellart, Francois J. L. Pein, Judith Raimbourg, Emilie Thibaudeau, Julie Paul, Olivier Glehen
Journal: Journal of Clinical Oncology (2024)

e15561 Background: Withmodern systemic chemotherapy, survival remain poor for patient withadvanced isolated peritoneal metastases from gastrointestinal tract. We aimed to assess the safety and efficacy of PIPAC to oxaliplatin in combination or not with systemic chemotherapy. Methods: We did a phase 1/2, open label, non-comparative, dose escalation and expansion trial of PIPAC to oxaliplatin forpatients with peritoneal cancer index (PCI) more than 5, 13 and 15 for respectively a gastric, small bowell and colorectal cancer primary; who had received at least three months of systemic chemotherapy. PIPAC cycle lengths was 4 to 6 weeks with systemic chemotherapy allowed 15 days after each PIPAC. PCI and oxaliplatin concentration tumor was assessed every PIPAC cycles. Main endpoints were, tolerability, tumor response and survival. Results: Between2017 to 2020, 34 for patients were enrolled in three centers, in this phase 1/2 study of whom 25 were evaluable at recommanded dose of phase I of 90 mg/m 2 plus systemic 5-FU. At this dose, safety profile showed acceptable tolerability. 8 patients (32%) had grade 3/4 treatment related adverse event. Minors (grade 1/2) adverse events were mainly abdominal pain (n = 19, 76%) and nausea (n = 16, 64%). Before inclusion patients received a median of 2 [1-4] chemotherapy lines and had a median PCI of 22.5 [7-29]. Median PFS was 6.1 months and median OS was 13 months. Conclusions: In patients with advanced and refractory peritoneal metastasis, PFS of 6.1 months is encouraging. A prospective randomized phase II study is required. Clinical trial information: NCT03294252 .
Preliminary results of atezolizumab and pirfenidone in non-small cell lung cancer.
Authors: Chao Hui Huang, Jo Wick, Takefumi Komiya
Journal: Journal of Clinical Oncology (2024)

e15197 Background: Checkpoint inhibitors (CPI) targeting the PD1/PD-L1 axis improved outcomes for stage IV non-small cell lung cancer (NSCLC). Poor response to PD-L1 antibody has been linked to increased cancer-associated fibroblasts (CAF), which interact with cytotoxic T cells (CTLs) similarly to regulatory T cells (Tregs). CAFs, through cytokine production, impair antitumor immunity by affecting CTL function (TGF beta) and inhibiting CTL recruitment into tumors, suggesting that CAFs could be a therapeutic target in CPI-resistant NSCLC. Pirfenidone (P) exhibits anti-fibrotic effects by blocking fibroblast differentiation into CAFs and suppressing TGF beta production and associated signaling pathways/collagens. Atezolizumab (A) targets PD-L1, inhibiting its interaction with PD-1 and B7-1 (CD80) receptors on T cells. We initiated a phase I/II trial to test the combination of AP in recurrent NSCLC after CPI progression. The phase I study aims to determine the maximum tolerated dose (MTD) of AP and assess its safety and tolerability. The phase II study will evaluate its efficacy. The Exploratory Objectives are to measure circulating levels of TGF beta and investigate the expression of CAF-related proteins. Methods: phase I will enroll 3 patients using P at 801 mg PO TID and A at 1200mg IV every 3 weeks. If there is ≤ 1 Dose Limiting Toxicity (DLT), the study will proceed to phase II. If there are ≥2 DLTs, P will be reduced to 534 mg TID. If there is ≤ 1 DLT at this dose, we will proceed to phase II. If there are ≥2 DLTs, then the study will be terminated. Phase II will enroll 16 patients to assess efficacy. The main inclusion criteria are patients with recurrent NSCLC without actionable mutation, after progression with first-line therapy CPI with or without platinum-based doublet chemotherapy, no more than 2 lines of therapy, measurable disease, ECOG 0-2, and adequate organ function. Results: The study enrolled a total of 5 patients (4 males, 1 female), median age of 63.4; 5 were white; 3 patients did not complete the required 21 days of therapy for evaluation (1 non-compliance, 1 disease progression,1 unrelated Urinary Tract Infection); 2 patients were evaluable for toxicity, without DLT; 1 exhibited a partial response to cutaneous metastatic disease, with overall stable disease, 1 had disease progression. Adverse events (AE) in more than 5% of patients included blood disorders, cardiac, gastrointestinal, administration site, metabolic, musculoskeletal, psychiatric, respiratory, and skin disorders. Serious AEs were noted in 2 patients: one experienced gastrointestinal bowel perforation due to disease progression resulting in death, and the other had a respiratory disorder. Conclusions: The combination of AP did not produce unexpected side effects or reach the dose-limiting toxicity threshold. After the phase I portion is completed, the study will proceed to phase II expansion to enroll patients with recurrent NSCLC. Clinical trial information: NCT04467723 .
Disease response of neoadjuvant chemoradiation guiding local excision approach in localized rectal cancer: A systematic review and meta-analysis of prospective data.
Authors: Davi Said Gonçalves Celso, Eduarda Dos Santos Lima, Luiza Giuliani Schmitt, Lucas Area Leao Barreto, Michel Fabiano Alves, Rafael Carvalho
Journal: Journal of Clinical Oncology (2024)

e15639 Background: Total Mesorectal Excision (with or without chemoradiation) has been the established standard of care for the treatment of localized rectal cancer. Neoadjuvant Chemoradiation (nCRT) followed by Local Excision (LE) has been proven as a safe alternative approach for selected patients. This study aims to review the current evidence of this strategy, guided by the disease response from the nCRT. Methods: database research was performed through PubMed, Embase, and Cochrane Central for prospective studies evaluating the use of nCRT followed by LE in localized rectal cancer patients. Our primary outcomes were Local Recurrence Rates (LRR) correlated to patients’ pathological response status. We pooled the proportions of binary outcomes and their 95% confidence intervals. I² analysis was used to assess heterogeneity. We performed statistical analyses using R software version 4.3.1 with a random-effects model. Our analysis was prospectively registered with the number CRD42024499095 (PROSPERO). Results: A pool of 760 citations was initially screened, and 5 prospective trials assessing nCRT following LE in at least one of the arms were selected with a pooled analysis of 438 patients (including CRT-LE single arm, or randomization with CRT followed by total mesorectal excision and short course radiation alone). Neoadjuvant treatment was performed with a radiation dose ranging between 45 - 54Gy and concomitant fluoropyrimidine (5-fluorouracil or Capecitabine) isolated or in combination with Oxaliplatin. The extracted data was subgrouped into favorable responders (FR) (complete or near-complete pathological response) or unfavorable responders (UR). Looking specifically at the nCRT+LE arm, 284 patients were identified, from which 168 were classified as FR (59.1%). The pooled LRR was 0.02 (95% CI 0.00-0.06; I² = 27%) for this group. A total of 116 patients were classified as UR, with a polled LRR of 0.09 (95% CI 0.05-0.16; I² = 0%). Conclusions: Our analysis demonstrate that nCRT + LE is a safe strategy, with data from 5 prospective trials demonstrating very low local recurrence rate, especially in the group of patients who achieved a good response to the neoadjuvant approach. Treatment intensification protocols aiming to achieve a higher response rate can potentially reduce the local recurrence in those patients.
The impact of socioeconomic status on gastrointestinal cancer care delivery in southeast Texas.
Authors: Ahmed Abdelhakeem, Junaid Anwar, Jacob Thompson, Telice Terro, Sara Henry, Samantha Blevins, Maryam Vasefi
Journal: Journal of Clinical Oncology (2024)

e15579 Background: Gastrointestinal (GI) cancers are a leading cause of cancer deaths in the US with an estimated 1,038,410 new cases and a 30.4% mortality rate in 2023. Disparities in cancer care are well documented and result from several variables, including socioeconomic status (SES), behavioral, and biological factors. We conducted a retrospective population-based cohort study aimed to investigate the relationship between various socioeconomic factors and delays in cancer treatment initiation, emphasizing the impact of gender, race, age, and geographical distance on the time to treatment initiation (TTI). Methods: We identified patients with colorectal, hepatobiliary, small intestinal, and gastroesophageal cancers, who received their cancer diagnosis and initiated treatment at Baptist Hospitals of Southeast Texas in Beaumont, Texas between January 2012, and December 2017. SES data, including age, sex, race, geographical distribution, insurance status, cancer staging, and treatment were collected. Logistic regression was performed to determine risk association by calculating odds ratios with 95% confidence intervals, as well as p-values to determine significance. The primary outcomes of interest were the overall survival (OS) rate, and TTI defined as the time interval between the confirmed cancer diagnosis and initiating the first treatment modality. Results: A total of 517 GI cancer patients were included in this study, with 359 comprising a cohort of patients with colorectal cancer. The majority of patients included were ; caucasians(%) males (%).. African American patients were significantly more likely to receive delayed treatment, Odds Ratio (OR): 5.89, 95% confidence interval (CI) 4.02-8.62, especially compared to the odds for similar Caucasian patients (OR: 0.16, CI: 0.11-0.23). When compared to younger counterparts, patients above the age of 80 were found to have poorer odds of prolonged survival (OR: 2.91, CI: 1.80-4.72). Patients who lived 30 miles away or further from our hospital had longer TTI compared to those living within 30 miles radius (OR: 1.85, CI: 1.19-2.87), a risk which remained significant within the colorectal cancer cohort (OR: 2.20, CI: 1.29-3.74). Patients with Medicare insurance showed longer TTI (OR: 1.50, CI: 1.01-2.23), and decreased OS (OR: 1.79, CI: 1.05-3.06)). No statistically significant difference was observed based on gender. Conclusions: Age, geographical location, and racial SES variables contribute to the disparities in GI cancer care in our community. Addressing these disparities and implementing targeted interventions to mitigate the impact of socioeconomic barriers is imperative to ensure equitable access to timely and effective cancer care, ultimately leading to improved patient outcomes and cancer survival rates.
Quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis of fruquintinib + best supportive care (BSC) compared with placebo + BSC in metastatic colorectal cancer (mCRC): Results from the FRESCO-2 trial.
Authors: Sebastian Stintzing, Josep Tabernero, Taroh Satoh, Arvind Dasari, Sara Lonardi, Cathy Eng, Rocio Garcia-Carbonero, Elena Elez, Takayuki Yoshino, Alberto F. Sobrero, James C. Yao, Stefan Kasper, Dirk Arnold, Edin Basic, Matthias Granold, Marco Petschulies, Liwen Wu, Lucy F. Chen, Zhao Yang, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2024)

e15554 Background: As mCRC and its treatment can adversely impact quality of life (QoL), maintaining QoL is an important treatment goal in addition to improving survival outcomes, particularly as patients progress through lines of therapy. In the global, randomized, double-blind, phase 3 FRESCO-2 trial (NCT04322539), fruquintinib (F) + BSC vs placebo (P) + BSC demonstrated significantly improved overall survival (OS) (median 7.4 months vs 4.8 months; HR 0.66, 95% confidence interval [CI] 0.55–0.80) and progression-free survival, with a manageable safety profile and without deterioration of QoL in heavily pretreated patients with refractory mCRC. The objective of this post-hoc Q-TWiST analysis was to assess the quality-adjusted survival benefit of F + BSC in the context of the FRESCO-2 trial. Methods: The Q-TWiST analysis was applied to all 691 randomized patients from FRESCO-2 (F + BSC n = 461 vs P + BSC n = 230). Survival time of each patient was partitioned into 3 health states: time spent with treatment-emergent adverse events of CTCAE grade 3 or 4 before disease progression (TOX), time before disease progression without toxicity (TWiST), and time between disease progression and death or censoring (REL). Assuming utility coefficients of 1 for TWIST and 0.5 for TOX and REL, Q-TWiST was calculated as the utility-weighted sum of the time spent in each health state. The mean time spent in each of the 3 health states was calculated for each treatment group using Kaplan-Meier analysis, and a 95% CI for the difference between treatment was calculated using the nonparametric bootstrap method. Results: Q-TWiST was 6.25 months for F + BSC and 4.21 months for P + BSC, a difference of 2.04 (95% CI 1.51–2.57) months longer with F + BSC vs P + BSC. This difference in Q-TWiST was mainly driven by the difference in the TWiST component (2.14 months [95% CI 1.78–2.49]; F + BSC 4.06 months vs P + BSC 1.92 months). The relative Q-TWiST gain, calculated as the difference in Q-TWiST divided by the mean OS time of the P + BSC group, was 31.4% in favor of F + BSC. Conclusions: In the FRESCO-2 trial, F + BSC demonstrated a clinically meaningful quality-adjusted survival benefit compared with P + BSC in heavily pretreated patients with refractory mCRC. Clinical trial information: NCT04322539 .
Effect of indole 3-propionic acid from microbiota on the immunity of CD8<sup>+</sup> T cell to improve chemotherapy of colorectal cancer.
Authors: Hongyu Xie, Haoyang Xu, Jinjie Wu, Jingyi Yang, Wanyi Zeng, Sanqing Jin, Zhen He, Ping Lan
Journal: Journal of Clinical Oncology (2024)

e15194 Background: Sensitivity of chemotherapy is a great challenge to improve the treatment efficacy in patients with colorectal cancer (CRC). Increasing study has revealed the role of microbiota in the modulation of chemotherapy sensitivity. However, the mechanism how microbiota regulates the efficacy of 5-fluorouracil (5-FU) is far from clear. Methods: We used germ-free mice and antibiotic-treated mice to demonstrate the impact of the gut microbiota on 5-FU sensitivity. Metabolomics analysis of serum from patients with CRC or mice experiments were applied to identify the key metabolite, indole 3-propionic acid (IPA). Specific pattern of microbiota with capability to produce IPA was revealed by metagenomics analysis of the mice feces. Single-cell RNA (scRNA) sequencing was subsequently used and antibody blockade experiments as well as T cell adoptive transfer experiment were conducted to confirm the role of CD8 + T cells in 5-FU treatment. AHR KO mice model was used to reveal how IPA regulate the immunity of CD8 + T cells. Engineering Escherichia coli strain BL21 with capability to produce IPA was constructed to modulate the chemotherapy sensitivity. Results: Decreased sensitivity of 5-FU chemotherapy was observed in both germ-free mice and antibiotic-treated mice models. Accumulation of serum IPA was found in mice with vancomycin intervention and verified in CRC patient with chemotherapy resistance. Additionally, metagenomic analysis of mice feces revealed that Clostridium sporogenes capable of producing IPA, are crucial for 5-FU chemotherapy sensitivity. Supplementation with IPA or Clostridium sporogenes could obviously improve the sensitivity of 5-FU chemotherapy. Subsequently scRNA sequencing analysis of tumor tissue revealed a higher infiltration of CD8 + T cells after IPA intervention. The role of IPA-induced CD8 + T cells in 5-FU treatment was confirmed by antibody blockade experiments and T cell adoptive transfer experiment. Further, improved therapeutic sensitivity by IPA and the infiltration of CD8 + T cells were vanished in AHR KO mice model. Biosynthesis of IPA by engineering bacteria was found to enhance the sensitivity of 5-FU chemotherapy. Conclusions: Indole 3-propionic acid from microbiota enhances the immunity of CD8+ T cell via activation of AHR signaling pathway, thus providing potential therapeutic strategies to improve the efficacy of chemotherapy in colorectal cancer.