Efficacy Of Chemotherapy In Colorectal Cancer Research Articles

Impact of proton pump inhibitors on pathologic response rates following fluoropyrimidine-based neoadjuvant chemotherapy in pancreatic cancer patients.

Proton pump inhibitors (PPIs) negatively impact fluoropyrimidine-based chemotherapy efficacy in colorectal cancer. This study assessed PPI impact on major pathologic response (mPR) rates of pancreatic adenocarcinoma (PDAC) patients receiving fluoropyrimidine-based chemotherapy. An institutional retrospective review of resected PDAC patients receiving neoadjuvant fluoropyrimidine-based chemotherapy (98% FOLFIRINOX) from 2011 to 2021 was conducted. Outcomes were stratified by use or nonuse of PPIs within 6 months of neoadjuvant chemotherapy initiation. Primary outcome was mPR defined as complete or near complete response. Among 540 patients included, the median age was 64 (IQR: 60-70) years, 297 (55%) were male, and 202 (37%) were PPI users. 170 (31%) patients had mPR with similar rates among PPI users and nonusers (29% vs. 33%, p = 0.38). No difference in mPR was seen between PPI users and nonusers receiving chemoradiation (35% vs. 36%, p = 0.89) or ≥8 cycles of NAC (33% vs. 36%, p = 0.55). Median OS for PPI users was 30.9 versus 31.7 months for nonusers (p = 0.62). On multivariable analysis, PPI therapy was not associated with decreased survival. PPI usage did not significantly influence mPR or OS following neoadjuvant fluoropyrimidine-based chemotherapy in resected PDAC patients. Further analysis of all patients, not just those who underwent resection, is required.

The efficacy of chemotherapy for colorectal cancer with early recurrence after adjuvant chemotherapy.

43 Background: Adjuvant chemotherapy is the standard treatment for patients with stage III colorectal cancer (CRC) underwent surgery.However, the efficacy of chemotherapy for early recurrence after adjuvant chemotherapy remains unclear. This study aimed to assess the efficacy of chemotherapy for CRC with early recurrence during or after adjuvant chemotherapy. Methods: We retrospectively reviewed CRC patients who underwent surgery at 3 institutions between 2016 and 2021. The inclusion criteria were as follows: ECOG performance status was 0 or 1, histology was adenocarcinoma, patients who received adjuvant chemotherapy following surgical resection, early recurrence during or within 12 months after adjuvant chemotherapy and no prior treatment for CRC after early recurrence. The interval from the last administration of adjuvant chemotherapy to recurrence was defined as the recurrence-free interval (RFI). Overall survival (OS), progression-free survival (PFS), objective response rates (ORR), and disease control rate (DCR) were assessed according to the RFI. Results: Of 448 patients, 32 patients were eligible. Median age was 57 years (range 26–79), 14 patients (44%) were male and ECOG performance status 0 / 1 was 29 (91%) / 3 (9%). RAS wild-type / mutant was 12 (38%) / 20 (62%) and right / left as sidedness was 21 (66%) / 11 (34%). Regarding adjuvant chemotherapy, 4 patients (12%) received single-agent therapy, while 28 patients (88%) received combination therapy with two agents. Palliative chemotherapy after early recurrence included Oxaliplatin-based regimens in 13 patients (41%), irinotecan-based regimens in another 13 patients (41%), and other regimens in 6 patients (18%). For all patients, the median PFS and OS were 10.4 months and 43.0 months, respectively. The ORR and DCR were 34.4% and 75.0%, respectively. When patients were divided into RFI < 6 months and RFI ≥ 6 months, the ORR was superior in the RFI ≥ 6 months group to RFI < 6 months group (56 % vs. 26%). The PFS (median 10.4 months vs. 17.8 months, HR 0.92; 95% Cl 0.36-2.38, p = 0.87) and OS (median 31.3 months vs. 43.0 months, HR 0.97; 95% Cl 0.31-3.08, p = 0.97) did not differ between the RFI < 6 months group and the RFI ≥ 6 months group. Multivariate analysis for OS indicated a trend toward a poor prognosis in the RFI < 6 months group compared to the RFI ≥ 6 months group (HR 1.78; 95% CI 0.35-8.98, p = 0.48). Conclusions: In patients with CRC experienced early recurrence, the RFI < 6 months group had a trend of poor efficacy compared to the RFI of ≥ 6 months group.

SRGAP2 controls colorectal cancer chemosensitivity via regulation of mitochondrial complex I activity.

Mitochondrial respiration and metabolism play an important role in the occurrence and development of colorectal cancer (CRC). In this study, we identified a functional pool of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2) in the mitochondria of CRC cells as an important regulator of CRC chemosensitivity. We found that SRGAP2 levels were increased in CRC cells in comparison to normal colorectal cells. Loss of mitochondrial SRGAP2 led to significant decrease in mitochondrial respiration and strongly sensitized the CRC cells to chemotherapy drugs. Mechanistically, SRGAP2 physically interacts with mitochondrial complex I and positively modulates its activity. In particular, chemosensitization upon SRGAP2 loss was phenocopied by the treatment of complex I inhibitor. Thus, our results demonstrate that SRGAP2 functions as a key regulator of CRC chemosensitivity, identifying SRGAP2 as a promising therapeutic target to enhance the efficacy of chemotherapy in CRC.

Mice with dysfunctional TGF-β signaling develop altered intestinal microbiome and colorectal cancer resistant to 5FU

Emerging data show a rise in colorectal cancer (CRC) incidence in young men and women that is often chemoresistant. One potential risk factor is an alteration in the microbiome. Here, we investigated the role of TGF-β signaling on the intestinal microbiome and the efficacy of chemotherapy for CRC induced by azoxymethane and dextran sodium sulfate in mice. We used two genotypes of TGF-β-signaling-deficient mice (Smad4+/− and Smad4+/−Sptbn1+/−), which developed CRC with similar phenotypes and had similar alterations in the intestinal microbiome. Using these mice, we evaluated the intestinal microbiome and determined the effect of dysfunctional TGF-β signaling on the response to the chemotherapeutic agent 5-Fluoro-uracil (5FU) after induction of CRC. Using shotgun metagenomic sequencing, we determined gut microbiota composition in mice with CRC and found reduced amounts of beneficial species of Bacteroides and Parabacteroides in the mutants compared to the wild-type (WT) mice. Furthermore, the mutant mice with CRC were resistant to 5FU. Whereas the abundances of E. boltae, B.dorei, Lachnoclostridium sp., and Mordavella sp. were significantly reduced in mice with CRC, these species only recovered to basal amounts after 5FU treatment in WT mice, suggesting that the alterations in the intestinal microbiome resulting from compromised TGF-β signaling impaired the response to 5FU. These findings could have implications for inhibiting the TGF-β pathway in the treatment of CRC or other cancers.

DJ‑1 is a new prognostic marker and predicts chemotherapy efficacy in colorectal cancer.

Protein/nucleic acid deglycase DJ-1 (DJ-1) is a 20-kDa conserved protein, which belongs to the DJ-1/ThiJ/Pfp I protein superfamily. Immunohistochemistry was performed to investigate the expression of DJ-1 in a colorectal cancer (CRC) tissue microarray containing tumor and corresponding adjacent normal tissues. In the present study, DJ-1 expression was significantly upregulated in CRC cells and tissues, compared with that in normal colon cells and adjacent normal tissues, respectively. In addition, patients with high DJ-1 expression levels had a worse overall survival (OS) compared with patients with low expression levels. Multivariate Cox regression analysis revealed that high DJ-1 expression levels was an independent prognostic factor for patients with CRC. Moreover, DJ-1 was able to regulate the PI3K/Akt/p27/cyclin E and PI3K/Akt/mTOR signaling pathways to promote CRC cell growth and metastasis in vitro and in vivo. In addition, DJ-1 regulated the NF-κB/Snail signaling pathway to induce CRC cell epithelial-mesenchymal transition to promote migration and invasion. Notably, patients receiving LFP treatment (oxaliplatin, 5-FU and tetrahydrofolate) had an increased OS compared with patients who underwent only surgery and low DJ-1 expression levels. The findings from the present study suggest that DJ-1 may serve as a promising prognostic marker and predicts chemotherapy efficacy in patients with CRC.

TRIM67 Activates p53 to Suppress Colorectal Cancer Initiation and Progression.

Tripartite motif (TRIM) family proteins participate in a variety of important cellular processes, including apoptosis, cell-cycle arrest, DNA repair, and senescence. In this study, we demonstrated that a novel TRIM family member, TRIM67, was commonly silenced in colorectal cancer and its downregulation was associated with poor survival. Trim67 knockout in ApcMin/+ mice increased the incidence, multiplicity, and burden of colorectal tumors. Similarly, colon-specific knockout of Trim67 significantly accelerated azoxymethane-induced colorectal cancer in mice. RNA sequencing revealed that the antitumor effect of TRIM67 was mediated by activation of the p53 signaling pathway. TRIM67 interacted directly with the C-terminus of p53, inhibiting p53 degradation by its ubiquitin ligase MDM2. TRIM67 was also a transcriptional target of p53; upon cellular stress, p53 bound to the TRIM67 promoter and induced significant upregulation of TRIM67, thereby forming a TRIM67/p53 self-amplifying loop that boosts p53-induced cell growth inhibition and apoptosis. Consequently, loss of this p53-positive regulatory program profoundly compromised p53-mediated responses to chemotherapy-induced DNA damage. Dampened p53 response was also observed in tumors of Trim67 knockout mice and Trim67 knockout embryonic fibroblasts. TRIM67 reactivation restored p53 activation and sensitized colorectal cancer cells to chemotherapy in vitro and in vivo. TRIM67 thus functions as a pivotal tumor suppressor in colorectal cancer and is a potential target for improving chemotherapy responsiveness. SIGNIFICANCE: The TRIM67/p53 axis represents a novel therapeutic target that could be harnessed to improve chemotherapy efficacy in colorectal cancer expressing wild-type p53 but with repressed p53 signaling.

Genetic variants in p53 signaling pathway genes predict chemotherapy efficacy in colorectal cancer.

BackgroundThe murine double minute‐2 gene (MDM2) was originally identified as predicting chemotherapy efficacy. However, little is known regarding the association between single nucleotide polymorphisms (SNPs) in the p53 signaling pathway and prognosis/chemotherapy sensitivity in colorectal cancer.MethodsWe analyzed the association between 111 SNPs in 22 p53 signaling pathway genes and both progression‐free survival (PFS) and disease control rate (DCR) using Cox regression and logistics regression analysis. The false discovery rate method was used for correction of multiple testing. Secondary structure was predicted by RNAfold. Expression qualitative trait locus analysis and mRNA expression differences were assessed using the GTEx and TCGA databases.ResultsWe found that the rs747828 C allele of TP73 was significantly associated with reduced PFS (HR = 1.64, 95% CI = 1.27‐2.12, P = 2.00 × 10−4) in the additive model. In the stratified analysis, the rs747828 C allele was significantly associated with both reduced PFS (P = 1.40 × 10−3) and DCR (P = 1.82 × 10−2) in oxaliplatin‐based chemotherapy. The secondary structure of TP73 was altered in response to different rs747828 genotypes. Although the rs747828 C allele was not associated with messenger RNA (mRNA) TP73 expression, it was significantly associated with increased mRNA TP73‐AS1 expression levels in sigmoid tissues. TP73 mRNA was significantly overexpressed in tumor tissues compared to adjacent normal tissues (P = 2.36 × 10−19).ConclusionOur findings indicate that functional genetic variants of TP73 mediate the response to chemotherapy in colorectal cancer.

Serum level of octanoic acid predicts the efficacy of chemotherapy for colorectal cancer.

The survival times of patients with advanced colorectal cancer (CRC) have increased due to the introduction of chemotherapy involving irinotecan and cetuximab. However, further studies are required on the effective pretreatment methods for identifying patients with CRC who would respond to particular treatments. The aim of the present study was to identify biomarkers for predicting the efficacy of chemotherapy for CRC. A total of 123 serum samples were collected from 31 patients with CRC just prior to each of the first four rounds of chemotherapy. Serum metabolome analysis was performed using a multiplatform metabolomics system, and univariate Cox regression hazards analysis of the time to disease progression was conducted. Octanoic acid and 1,5-anhydro-D-glucitol were identified as biomarker candidates. In addition, the serum level of octanoic acid was indicated to be significantly associated with the time to disease progression (hazard ratio, 3.3; 95% confidence interval, 1.099–11.840; P=0.033). The serum levels of fatty acids, in particular polyunsaturated fatty acids, tended to be downregulated in the partial response group. The findings of the present study suggest that the serum level of octanoic acid may serve as a useful predictor for the prognosis of CRC.

Overcoming P-Glycoprotein-Mediated Multidrug Resistance in Colorectal Cancer: Potential Reversal Agents among Herbal Medicines.

Objectives Multidrug resistance (MDR) is the major reason for the failure of chemotherapy in colorectal cancer (CRC), and the primary determinant of MDR in CRC patients is active drug efflux owing to overexpression of P-glycoprotein (P-gp) in cancer tissues. Despite research efforts to overcome P-gp-mediated drug efflux, the high toxicity of P-gp inhibitors has been a major obstacle for the clinical use of these agents. The aim of this study was to review the literature for potential P-gp reversal agents among traditional herbal medicines, which offer the advantages of safety and potential synergetic effects in CRC chemotherapy. Methods We searched ten databases including 3 English databases, 1 Chinese medical database, and 6 Korean medical databases up to July 2018 and included in vivo and in vitro studies evaluating the effects of herbal medicines as P-gp reversal agents in CRC. Results A total of 28 potentially related studies were identified and 16 articles were included. Involving 3 studies about Salvia miltiorrhiza and 2 studies about Curcuma longa, finally we found 14 kinds of traditional herbal medicines—Salvia miltiorrhiza, Curcuma longa, Sinomenium acutum, Stephania tetrandra, Bufo gargarizans, Coptis japonica, Piper nigrum and Piper longum, Hedyotis diffusa, Schisandra chinensis, Glycyrrhiza glabra, Glycyrrhiza inflate, Daphne genkwa, Stemona tuberosa Lour, and Andrographis paniculata—as showing efficacy as P-gp inhibitors in anticancer drug-resistant CRC cells in vitro and in vivo. Conclusions This brief account provides insight into the relationship between P-gp and CRC. Further studies on herbal medicines with demonstrated effects against P-gp overexpression will aid in improving the efficacy of chemotherapy in CRC.

Predictive Biomarkers of Chemotherapy Efficacy in Colorectal Cancer: Results From the UK MRC FOCUS Trial

Candidate predictive biomarkers for irinotecan and oxaliplatin were assessed in 1,628 patients in Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (FOCUS), a large randomized trial of fluorouracil alone compared with fluorouracil and irinotecan and compared with fluorouracil and oxaliplatin in advanced colorectal cancer. The candidate biomarkers were: tumor immunohistochemistry for MLH1/MSH2, p53, topoisomerase-1 (Topo1), excision repair cross-complementing gene 1 (ERCC1), O-6-methylguanine-DNA-methyltranserase (MGMT), and cyclooxygenase 2 (COX2); germline DNA polymorphisms in GSTP1, ABCB1, XRCC1, ERCC2, and UGT1A1. These were screened in more than 750 patients for interaction with benefit from irinotecan or oxaliplatin; two markers (Topo1 and MLH1/MSH2) met criteria to be taken forward for analysis in the full population. Primary end points were progression-free survival (PFS) and overall survival. One thousand three hundred thirteen patients (81%) were assessable for Topo1 immunohistochemistry (low, < 10%; moderate, 10% to 50%; or high, > 50% tumor nuclei). In patients with low Topo1, PFS was not improved by the addition of either irinotecan (hazard ratio [HR], 0.98; 95% CI, 0.78 to 1.22) or oxaliplatin (HR, 0.85; 95% CI, 0.68 to 1.07); conversely, patients with moderate/high Topo1 benefited from the addition of either drug (HR, 0.48 to 0.70 in all categories; interaction P = .005; overall, P = .001 for irinotecan; P = .05 for oxaliplatin). High Topo1 was associated with a major overall survival benefit with first-line combination chemotherapy (HR, 0.60; median benefit, 5.3 months); patients with moderate or low Topo1 did not benefit (HR, 0.92 and 1.09, respectively; interaction P = .005). MLH1/MSH2 did not show significant interaction with treatment, although the low rate of loss (4.4%) limits the power of the study for this biomarker. Topo1 immunohistochemistry identified subpopulations that did or did not benefit from irinotecan, and possibly also from oxaliplatin. If verified independently, this information will contribute to the individualization of treatment for colorectal cancer.

Microsatellite instability as a predictor of chemotherapy efficacy in colorectal cancer

4117 Background: Microsatellite instability (MSI) status is a prognostic factor in colorectal cancer (CRC), but its ability to predict chemotherapy (CT) efficacy either in adjuvant or metastatic se...