Cytochrome P450 content in primary tumors and liver metastases of patients with metastatic colorectal cancer

2020 ◽  
Vol 42 (4) ◽  
Keyword(s):  
Colorectal Cancer ◽  
Cytochrome P450 ◽  
Liver Metastases ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumors ◽  
Cytochrome P450 Content

scholarly journals Discordance of KRAS Mutational Status between Primary Tumors and Liver Metastases in Colorectal Cancer: Impact on Long-Term Survival Following Radical Resection

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2148
Author(s):  
Francesco Ardito ◽  
Francesco Razionale ◽  
Lisa Salvatore ◽  
Tonia Cenci ◽  
Maria Vellone ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Primary Tumor ◽  
Kras Mutation ◽  
Colorectal Tumor ◽  
Term Survival ◽  
Primary Tumors ◽  
Mutation Status ◽  
Primary Colorectal Tumor ◽  
Kras Mutation Status

If KRAS mutation status of primary colorectal tumor is representative of corresponding colorectal liver metastases (CRLM) mutational pattern, is controversial. Several studies have reported different rates of KRAS discordance, ranging from 4 to 32%. Aim of this study is to assess the incidence of discordance and its impact on overall survival (OS) in a homogenous group of patients. KRAS mutation status was evaluated in 107 patients resected for both primary colorectal tumor and corresponding CRLM at the same institution, between 2007 and 2018. Discordance rate was 15.9%. Its incidence varied according to the time interval between the two mutation analyses (p = 0.025; Pearson correlation = 0.2) and it was significantly higher during the first 6 months from the time of primary tumor evaluation. On multivariable analysis, type of discordance (wild-type in primary tumor, mutation in CRLM) was the strongest predictor of poor OS (p < 0.001). At multivariable logistic regression analysis, the number of CRLM >3 was an independent risk factor for the risk of KRAS discordance associated with the worst prognosis (OR = 4.600; p = 0.047). Results of our study suggested that, in the era of precision medicine, possibility of KRAS discordance should be taken into account within multidisciplinary management of patients with metastatic colorectal cancer.

Regorafenib plus PD-1 inhibitors in Chinese patients with microsatellite stable/mismatch repair proficient metastatic colorectal cancer: A real-world study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15585-e15585
Author(s):  
Kaili Yang ◽  
Lu Han ◽  
Yun-Bo Zhao ◽  
Yang Ge ◽  
Qin LI ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Real World ◽  
Objective Response ◽  
Disease Control Rate ◽  
Chinese Patients ◽  
Hand Foot Syndrome

e15585 Background: A previous phase 1b trial has shown encouraging efficacy of regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair proficient (MSS/pMMR) metastatic colorectal cancer (mCRC). We aimed to evaluate the efficacy and safety of this regimen in Chinese patients in the real world. Methods: We retrospectively identified patients with MSS/pMMR mCRC who received at least one dose of programmed cell death-1 (PD-1) inhibitors plus regorafenib from 5/2019 to 2/2021 in 10 Chinese medical centers. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and the safety. Results: Fifty-two patients were identified. Liver metastases were presented in 35 patients (67%). A total of 48 patients (92%) received regorafenib plus a PD-1 inhibitor as the third or later line treatment. At the data cut-off, 11 patients (21%) were still on treatment. Other patients terminated treatment because of progressive disease (45%), treatment-related adverse events (TRAEs) (14%) or treatment-unrelated deaths (6%). The median treatment cycle was 3 (range, 1-18). At a median follow-up of 4.9 months, the median OS was 17.3 months (95% CI, 10.2-NR) and the median PFS was 3.1 months (95%CI, 2.5-6.0). Baseline liver metastases were associated with inferior PFS (2.7 versus 6.3 months, p <0.05), but not OS (17.3 months versus NR, p =0.6). Among 38 patients evaluable for response, two patients (5%) achieved partial response, and 17 patients (45%) experienced stable disease as the best response. The DCR was 50% (95%CI, 5.0-NR) and was similar among different PD-1 inhibitors (Table). TRAEs were observed in 30 patients (58%). Fatigue (21%), hand-foot syndrome (19%) and rash (13%) were the most common TRAEs. Eight patients (15%) experienced grade 3-4 TRAEs, including rash (n=3), hand-foot syndrome (n=2), hypertension (n=1), myocardial enzyme elevation (n=1) and visual field loss (n=1). No treatment-related death occurred. Conclusions: The combination of regorafenib plus PD-1 inhibitors was generally tolerated and exhibited potential benefit in terms of OS and DCR. The presence of baseline liver metastases was predictive for shorter PFS but requires further investigation. Disease control rate of different PD-1 inhibitors.[Table: see text]

scholarly journals Clinical and molecular determinants of extrahepatic disease progression in patients with metastatic colorectal cancer with liver-limited metastases deemed initially unresectable

ESMO Open ◽  
2019 ◽  
Vol 4 (2) ◽  
pp. e000496
Author(s):  
Elena Ongaro ◽  
Chiara Cremolini ◽  
Daniele Rossini ◽  
Francesca Corti ◽  
Filippo Pagani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Progression Free Survival ◽  
Extrahepatic Disease ◽  
Nodal Involvement ◽  
Liver Resections ◽  
Multicentre Cohort Study ◽  
Molecular Determinants

BackgroundNo tools to predict the probability of extrahepatic disease progression (ePD) of initially unresectable, liver-limited metastatic colorectal cancer (mCRC) are currently available. To estimate the likelihood to develop ePD and to identify clinical and molecular factors that could predict extrahepatic progression-free survival (ePFS), we conducted an observational, retrospective, multicentre cohort study.MethodsWe retrospectively identified a cohort of 225 patients with initially unresectable liver-limited disease (LLD), treated from January 2004 to December 2017 with first-line doublets or triplet plus a biological agent at two Italian institutions.Results173 (77%) patients experienced ePD which occurred within 1, 2 or 3 years from the diagnosis of mCRC in 15%, 49% and 66% of patients, respectively. Globally, 164 (73%) patients underwent a liver resection at some point of their disease history, and 54 (33%) of them underwent a subsequent locoregional treatment. Age > 70 years, locoregional nodal involvement at diagnosis of colorectal cancer and ≥4 liver metastases were significantly associated with higher risk of ePD while liver resections were associated with reduced risk of ePD. In the multivariable model, number of liver metastases (subdistribution HR, SHR 1.63, 95% CI 1.12 to 2.36; p = 0.01) and liver resections (SHR 0.43, 95% CI 0.29 to 0.63; p = 0.001) were still associated with ePD. Number of liver metastases < 4, no nodal involvement at diagnosis and liver resections were also associated with prolonged ePFS.ConclusionsThe identified clinical factors could help physicians in personalising the intensity and aggressiveness of liver-directed treatments in patients with mCRC with initially unresectable LLD.

scholarly journals Bevacizumab Maintenance Versus No Maintenance During Chemotherapy-Free Intervals in Metastatic Colorectal Cancer: A Randomized Phase III Trial (PRODIGE 9)

2018 ◽  
Vol 36 (7) ◽  
pp. 674-681 ◽  
Author(s):  
Thomas Aparicio ◽  
Francois Ghiringhelli ◽  
Valérie Boige ◽  
Karine Le Malicot ◽  
Julien Taieb ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Induction Chemotherapy ◽  
Controlled Trial ◽  
Performance Status ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Tumor Control ◽  
Primary Tumors

Purpose Conflicting results are reported for maintenance treatment with bevacizumab during chemotherapy-free intervals (CFI) in metastatic colorectal cancer after induction chemotherapy. Patients and Methods In this open-label, phase III, randomized controlled trial, we compared the tumor control duration (TCD) observed with bevacizumab maintenance and with no treatment (observation) during CFI subsequent to induction chemotherapy with 12 cycles of fluorouracil, leucovorin, and irinotecan plus bevacizumab. After disease progression, the induction regimen was repeated for eight cycles, followed by a new CFI. Results From March 2010 to July 2013, 491 patients were randomly assigned. Disease progression or death occurred during induction chemotherapy in 85 patients (17%); 261 patients (53%) had at least one reinduction, 107 (22%) had two reinductions, and 56 (11%) had three or more reinductions. The median TCD was 15 months in both groups; the median progression-free survival (PFS) from randomization was 9.2 and 8.9 months in the maintenance group and observation groups, respectively. The TCD observed in both groups was higher compared with the TCD hypotheses of the trial. The median overall survival (OS) was 21.7 and 22.0 months in the maintenance and observation groups, respectively. In the per-protocol population, defined as patients with at least one reinduction after the first progression, the median duration of the first CFI was 4.3 months in both arms; the median TCD was 17.8 and 23.3 months ( P = .339), the median PFS was 9.9 and 9.5 months, and the median OS was 27.6 and 28.5 months in the maintenance and observation groups, respectively. Multivariable analysis revealed that female gender, WHO performance status ≥ 2, and unresected primary tumors were associated with a shorter TCD. Conclusion Bevacizumab maintenance monotherapy did not improve TCD, CFI duration, PFS, or OS.

Predictive significance of VEGF and HIF-1α expression in metastatic colorectal cancer patients receiving chemotherapy combined with bevacizumab.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14672-e14672
Author(s):  
Veli Berk ◽  
Kemal Deniz ◽  
Halit Karaca ◽  
Mevlude Inanc ◽  
Oktay Bozkurt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Clinical Benefit ◽  
Hypoxia Inducible Factor ◽  
Therapy Response ◽  
Progression Free Survival ◽  
Vegf Expression ◽  
Primary Tumors ◽  
Colorectal Cancer Patients ◽  
Low Expression

e14672 Background: There is no suggested molecular indicator in identifying which patients will benefit from anti-angiogenic treatment in metastatic colorectal cancer. Over expression of vascular endothelial growth factor (VEGF) and Hypoxia Inducible Factor 1-alpha (HIF-1α) are associated with bad prognosis. In this study, VEGF and HIF-1α expression and their clinical significance are studied in tumor tissues of patients with colorectal cancer receiving treatment with bevacizumab. Methods: VEGF and HIF-1α were observed immunohistochemically in primary tumors of 53 patients. The expressions were separated by evaluating low and high of VEGF and HIF-1α expression. We evaluated whether expression of VEGF and HIF-1α can help to predict treatment response, progression free survival (PFS), and overall survival (OS). Results: Fifty-three patients were enrolled in the study. Median age was 55. VEGF was strongly expressed in 30 patients (57%) whilst low expression was observed in 23 of them (43%). When VEGF expression was evaluated in association with therapy response rates; the clinical benefit rate was 38% in the low expression group whereas it was 62% in high expression group. This difference was statistically significant (p=0.01). In the group with strong VEGF expression PFS was 10 months whereas it was 8 months in the low expression group (p=0.009). When evaluated for OS, 26 months versus 15 months was in favor of highly expressed VEGF group (p=0.03). Highly expressed HIF-1α was found in 29 patients (55%), on the other hand low expressed HIF-1α was detected in 24 (%45) patients. For clinical benefit rates, PFS and OS there was no difference between high and low expressed HIF-1α groups. Conclusions: It has been demonstrated that VEGF and HIF-1α expressions are associated with poor prognosis in several tumors, mainly colorectal carcinomas. With the better understanding of carciogenesis and angiogenesis at molecular level, especially VEGF and HIF-1α became target molecules of the therapy. According to results of our study, VEGF expression is a predictive factor in designating the metastatic colorectal cancer treatment.

Increased gene copy number and amplification of FGF2 and FGFR1 in metastatic colorectal cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 402-402 ◽  
Author(s):  
Christopher Hanyoung Lieu ◽  
Marileila Varella-Garcia ◽  
Liang Guo Xu ◽  
Zhi-Qin Jiang ◽  
S. Gail Eckhardt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Metastatic Colorectal Cancer ◽  
Copy Number ◽  
Resistance Mechanism ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Cell Range ◽  
Previously Treated ◽  
Fgfr1 Gene

402 Background: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play essential roles in tightly regulating cell proliferation, survival, migration, and angiogenesis in cancers. However, gene copy number and amplification of FGF2 and FGFR1 have not been extensively evaluated in patients with metastatic colorectal cancer (CRC). Methods: Two tissue microarrays (TMA) were constructed with resected CRC liver metastases from 120 patients. The TMAs included duplicated intratumoral regions and the invasive margin between tumor and normal hepatic parenchyma. Patients were either untreated, or previously treated with FOLFIRI or FOLFOX +/- bevacizumab. The TMA slides were subjected to a two-color FISH assay using a mixture of FGF2 and FGFR1 in-house developed probes. Results: Results were obtained from 118 patients. The analysis detected an average of 1.90 copies of FGF2 signal per cell (range, 1.10-3.46 copies) and an average of 2.27 copies of FGFR1 signal per cell (range, 1-12-7.14 copies). Three control specimens from each slide were also scored, with an average of 1.74 copies of FGF2 and 1.73 copies of FGFR1. High copy number per cell (mean > 2.5 copies) was detected in 9.3% of specimens for FGF2 and 27.9% for FGFR1, including 2 patients (1.7%) for FGF2 and 5 (4.2%) for FGFR1 with focal amplification, defined by ≥ 10% cells with > 4 copies. Additionally, duplications of gene signals in the same locus were detected in 10 samples (8.5%) for FGF2 and 19 (16.1%) for FGFR1. Intratumoral heterogeneity was rare (detected in 3 patients). There was no statistically significant correlation between FGF2 or FGFR1 gene copy number and prior treatment, pathologic response, relapse free survival, or overall survival, though there was a trend towards higher FGFR1 gene copy number in patients previously receiving bevacizumab (p=0.07). Conclusions: Both FGF2 and FGFR1 display variable copy number among resected CRC liver metastases, with larger variability detected for FGFR1. Gene amplification was rare but detected in several patients for both FGF2 and FGFR1. Follow up studies will investigate higher FGFR1 gene copy number in patients previously treated with bevacizumab, perhaps reflecting a potential escape or resistance mechanism.

Impact of primary tumor sidedness on erlotinib efficacy in patients with metastatic colorectal cancer treated with bevacizumab maintenance: Results from the DREAM phase III trial.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 737-737 ◽  
Author(s):  
Benoist Chibaudel ◽  
Thierry Andre ◽  
Benoit Samson ◽  
Marie-Line Garcia-Larnicol ◽  
Jérôme Dauba ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibodies ◽  
Maintenance Therapy ◽  
Metastatic Colorectal Cancer ◽  
Clinical Outcomes ◽  
Primary Tumor ◽  
Phase Iii ◽  
Primary Tumors ◽  
Phase Iii Trial ◽  
Mutational Status

737 Background: Primary tumor sidedness (PTS) could be a predictive maker for treatment efficacy of EGFR inhibitors monoclonal antibodies in patients with wild-type (WT) RAS metastatic colorectal cancer (MCRC), cetuximab having limited efficacy in patients with WT-RAS right-sided tumors. DREAM study demonstrated that adding erlotinib, an oral EGFR tyrosine kinase inhibitor (TKI) to bevacizumab during maintenance therapy improved clinical outcomes (RR, PFS, OS) in patients with MCRC, whatever KRAS status. The aim of this post-hoc analysis is to evaluate the clinical outcomes according to KRAS mutational status and PTS when adding erlotinib to bevacizumab maintenance therapy. Methods: PTS was retrospectively collected in patients from the DREAM phase III trial treated with bevacizumab with or without erlotinib as maintenance therapy for MCRC who have been controlled by induction therapy. The limit for the definition of PTS was splenic flexure, and rectal tumors were considered as left-sided tumors. The primary endpoint was overall survival (OS). Results: Among 452 patients who received maintenance therapy, PTS ascertainment was 84.7% (n = 383) with 265 (71.0%) patients having left-sided primary tumor and 108 (28.9%) having right-sided primary tumors (3 patients had both and tumor location was unknown in 7 patients). Median OS and treatment effect are presented in table 1. Conclusions: The greatest OS benefit of adding erlotinib to bevacizumab maintenance therapy was observed in patients with WT-KRAS and right-sided MCRC, suggesting a clinical impact of the different mechanism of action between EGFR TKI and monoclonal antibodies. Clinical trial information: NCT00265824. [Table: see text]

A phase II study investigating cabozantinib in patients with refractory metastatic colorectal cancer (AGICC 17CRC01).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 103-103
Author(s):  
Aaron James Scott ◽  
Steven J. Cohen ◽  
Atrayee Basu Mallick ◽  
Efrat Dotan ◽  
Philip Jordan Gold ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Alternative Hypothesis ◽  
Pik3ca Mutation ◽  
Phase Iii ◽  
Type I ◽  
Primary Tumors

103 Background: Therapeutic resistance to antiangiogenics in metastatic colorectal cancer (mCRC) inevitably develops via multiple mechanisms including upregulation of the MET kinase pathway. Cabozantinib, an oral multityrosine kinase inhibitor targeting MET, AXL, and VEGFR, demonstrated significant anti-tumor activity in CRC xenograft and cell line models. Methods: A single-arm, two-stage phase II study was conducted at 7 AGICC centers nationwide. 44 patients (pts) with mCRC who had progressed on or were intolerant of standard of care agents were treated with cabozantinib 60 mg daily in q3 wk cycles. The primary endpoint was 12-wk PFS rate. Based on the control arm of phase III CORRECT study, the Kaplan-Meier 12-wk PFS rate estimate was 13% and served as the null hypothesis. This study was powered at 0.906 to detect the alternative hypothesis of 12-wk PFS rate of 33% with a type I error rate of 0.044. Secondary endpoints were safety, RR, OS, and retrospective analysis of PFS and RR based on RAS, BRAF, and PIK3CA mutation status. Results: 44 pts were enrolled and 34 pts were response-evaluable as having undergone at least the first 6-wk restaging scan. 10 pts discontinued treatment prior to the first 6-wk scan due to clinical disease progression. Median number of cycles was 4 and median follow-up was 2.5 months. As of data-cutoff 8/23/2019, 55 Grade 3/4 AEs were reported with the most common being hypertension, fatigue, diarrhea, pain, HFS, nausea, vomiting, and proteinuria. 32 SAEs occurred in 18 pts. 5 Grade 5 AEs were reported: disease progression (3), disseminated intravascular coagulopathy, and bowel perforation. 15 pts (34%) achieved ≥ 12-wk PFS and 8 patients remain on treatment. Best response was 1 PR and 31 SD with a DCR at 6 wks of 72.7%. Of the pts who achieved ≥ 12-wk PFS, 12 had left-sided primary tumors, 5 had a RAS mutation, 1 had a PIK3CA mutation, and all pts were BRAF WT and MSI stable. Conclusions: Cabozantinib was deemed safe and demonstrates encouraging efficacy in a heavily pretreated mCRC pt population. These results support further investigation of cabozantinib in mCRC. Clinical trial information: NCT03542877.

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